Substituted cyclobutylbenzene compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

ABSTRACT

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: (Formula (I)). Also disclosed herein are uses of a compound disclosed herein in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising a compound disclosed herein. Further disclosed herein are uses of a composition in the potential treatment or prevention of an IDO-associated disease or disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the 371 national phase application ofInternational Application No. PCT/US2018/054273, filed Oct. 4, 2018,which claims the benefit of U.S. Provisional Application No. 62/569,874,filed Oct. 9, 2017, hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Tryptophan (Trp) is an essential amino acid required for thebiosynthesis of proteins, niacin and the neurotransmitter5-hydroxytryptamine (serotonin). The enzyme indoleamine 2,3-dioxygenase(IDO) catalyzes the first and rate limiting step in the degradation ofL-tryptophan to N-formyl-kynurenine. In human cells, a depletion of Trpresulting from IDO activity is a prominent gamma interferon(EFN-γ)-inducible antimicrobial effector mechanism. IFN-γ stimulationinduces activation of IDO, which leads to a depletion of Trp, therebyarresting the growth of Trp-dependent intracellular pathogens such asToxoplasma gondii and Chlamydia trachomatis. IDO activity also has anantiproliferative effect on many tumor cells, and IDO induction has beenobserved in vivo during rejection of allogeneic tumors, indicating apossible role for this enzyme in the tumor rejection process (Daubener,et al, 1999, Adv. Exp. Med. Biol, 467: 517-24; Taylor, et al, 1991,FASEB J., 5: 2516-22).

It has been observed that HeLa cells co-cultured with peripheral bloodlymphocytes (PBLs) acquire an immuno-inhibitory phenotype throughup-regulation of IDO activity. A reduction in PBL proliferation upontreatment with interleukin-2 (IL2) was believed to result from IDOreleased by the tumor cells in response to IFN-γ secretion by the PBLs.This effect was reversed by treatment with 1-methyl-tryptophan (IMT), aspecific IDO inhibitor. It was proposed that IDO activity in tumor cellsmay serve to impair antitumor responses (Logan, et al, 2002, Immunology,105: 478-87).

Several lines of evidence suggest that IDO is involved in induction ofimmune tolerance. Studies of mammalian pregnancy, tumor resistance,chronic infections and autoimmune diseases have shown that cellsexpressing IDO can suppress T-cell responses and promote tolerance.Accelerated Trp catabolism has been observed in diseases and disordersassociated with cellular immune activation, such as infection,malignancy, autoimmune diseases and AIDS, as well as during pregnancy.For example, increased levels of IFNs and elevated levels of urinary Trpmetabolites have been observed in autoimmune diseases; it has beenpostulated that systemic or local depletion of Trp occurring inautoimmune diseases may relate to the degeneration and wasting symptomsof these diseases. In support of this hypothesis, high levels of IDOwere observed in cells isolated from the synovia of arthritic joints.IFNs are also elevated in human immunodeficiency virus (HIV) patientsand increasing IFN levels are associated with a worsening prognosis.Thus, it was proposed that IDO is induced chronically by HIV infection,and is further increased by opportunistic infections, and that thechronic loss of Trp initiates mechanisms responsible for cachexia,dementia and diarrhea and possibly immunosuppression of AIDS patients(Brown, et al., 1991, Adv. Exp. Med. Biol, 294: 425-35). To this end, ithas recently been shown that IDO inhibition can enhance the levels ofvirus-specific T cells and, concomitantly, reduce the number ofvirally-infected macrophages in a mouse model of HIV (Portula et al.,2005, Blood, 106: 2382-90).

IDO is believed to play a role in the immunosuppressive processes thatprevent fetal rejection in utero. More than 40 years ago, it wasobserved that, during pregnancy, the genetically disparate mammalianconceptus survives in spite of what would be predicted by tissuetransplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7:320-38).

Anatomic separation of mother and fetus and antigenic immaturity of thefetus cannot fully explain fetal allograft survival. Recent attentionhas focused on immunologic tolerance of the mother. Because IDO isexpressed by human syncytiotrophoblast cells and systemic tryptophanconcentration falls during normal pregnancy, it was hypothesized thatIDO expression at the maternal-fetal interface is necessary to preventimmunologic rejection of the fetal allografts. To test this hypothesis,pregnant mice (carrying syngeneic or allogeneic fetuses) were exposed toIMT, and a rapid, T cell-induced rejection of all allogeneic conceptionwas observed. Thus, by catabolizing tryptophan, the mammalian conceptusappears to suppress T-cell activity and defends itself againstrejection, and blocking tryptophan catabolism during murine pregnancyallows maternal T cells to provoke fetal allograft rejection (Moan, etal., 1998, Science, 281: 1191-3).

Further evidence for a tumoral immune resistance mechanism based ontryptophan degradation by IDO comes from the observation that most humantumors constitutively express IDO, and that expression of IDO byimmunogenic mouse tumor cells prevents their rejection by preimmunizedmice. This effect is accompanied by a lack of accumulation of specific Tcells at the tumor site and can be partly reverted by systemic treatmentof mice with an inhibitor of IDO, in the absence of noticeable toxicity.Thus, it was suggested that the efficacy of therapeutic vaccination ofcancer patients might be improved by concomitant administration of anIDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It hasalso been shown that the IDO inhibitor, 1-MT, can synergize withchemotherapeutic agents to reduce tumor growth in mice, suggesting thatIDO inhibition may also enhance the anti-tumor activity of conventionalcytotoxic therapies (Muller et al, 2005, Nature Med., 11: 312-9).

One mechanism contributing to immunologic unresponsiveness toward tumorsmay be presentation of tumor antigens by tolerogenic host APCs. A subsetof human IDO-expressing antigen-presenting cells (APCs) that coexpressedCD 123 (IL3RA) and CCR6 and inhibited T-cell proliferation have alsobeen described. Both mature and immature CD123-positive dendritic cellssuppressed T-cell activity, and this IDO suppressive activity wasblocked by 1MT (Munn, et al, 2002, Science, 297: 1867-70). It has alsobeen demonstrated that mouse tumor-draining lymph nodes (TDLNs) containa subset of plasmacytoid dendritic cells (pDCs) that constitutivelyexpress immunosuppressive levels of IDO. Despite comprising only 0.5% oflymph node cells, in vitro, these pDCs potently suppressed T cellresponses to antigens presented by the pDCs themselves and also, in adominant fashion, suppressed T cell responses to third-party antigenspresented by nonsuppressive APCs. Within the population of pDCs, themajority of the functional IDO-mediated suppressor activity segregatedwith a novel subset of pDCs coexpressing the B-lineage marker CD19.Thus, it was hypothesized that IDO-mediated suppression by pDCs in TDLNscreates a local microenvironment that is potently suppressive of hostantitumor T cell responses (Munn, et al., 2004, J. Clin. Invest, 114(2):280-90).

IDO degrades the indole moiety of tryptophan, serotonin and melatonin,and initiates the production of neuroactive and immunoregulatorymetabolites, collectively known as kynurenines. By locally depletingtryptophan and increasing proapoptotic kynurenines, IDO expressed bydendritic cells (DCs) can greatly affect T-cell proliferation andsurvival. IDO induction in DCs could be a common mechanism of deletionaltolerance driven by regulatory T cells. Because such tolerogenicresponses can be expected to operate in a variety of physiopathologicalconditions, tryptophan metabolism and kynurenine production mightrepresent a crucial interface between the immune and nervous systems(Grohmann, et al, 2003, Trends Immunol, 24: 242-8). In states ofpersistent immune activation, availability of free serum Trp isdiminished and, as a consequence of reduced serotonin production,serotonergic functions may also be affected (Wirleitner, et al., 2003,Curr. Med. Chem., 10: 1581-91).

In light of the potential role for IDO in immunosuppression, tumorresistance and/or rejection, chronic infections, HIV-infection, AIDS(including its manifestations such as cachexia, dementia and diarrhea),autoimmune diseases or disorders (such as rheumatoid arthritis), andimmunologic tolerance and prevention of fetal rejection in utero,therapeutic agents aimed at suppression of tryptophan degradation byinhibiting IDO activity are desirable. Inhibitors of IDO can be used toactivate T cells and therefore enhance T cell activation when the Tcells are suppressed by pregnancy, malignancy or a virus such as HIV.Inhibition of IDO may also be an important treatment strategy forpatients with neurological or neuropsychiatric diseases or disorderssuch as depression. Compounds disclosed herein are useful in thepotential treatment or prevention of IDO-related diseases.

SUMMARY OF THE INVENTION

Disclosed herein are novel compounds of formula (I), which areinhibitors of the IDO enzymes. Also disclosed herein are uses of thesecompounds in the potential treatment or prevention of an IDO-associateddisease or disorder. Also disclosed herein are compositions comprisingone or more of the compounds. Further disclosed herein are uses of thesecompositions in the potential prevention or treatment of anIDO-associated disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein is a compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

wherein:L is selected from (1) a bond, (2) —NHC(O)— and (3) —C(O)NH—;W is selected from (1) —C(O)NH— and (2) —NHC(O)—;R¹ is selected from:

-   -   (1) C₁₋₆ alkyl,    -   (2) C₃₋₆ cycloalkyl,    -   (3) aryl, and    -   (4) heterocyclyl;    -   wherein the C₁₋₆ alkyl of (1) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b) C₃₋₆        cycloalkyl, and (c) —O—C₁₋₆ alkyl; and    -   wherein each of the C₃₋₆ cycloalkyl of (2), aryl of (3), and        heterocyclyl of (4) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b) C₃₋₆        cycloalkyl, (c) —CN, (d) —O—C₁₋₆ alkyl, and (e) C₁₋₆ alkyl        optionally substituted with 1-3 substituents independently        selected from halogen and —NH₂;        R² is selected from:    -   (1) C₁₋₆ alkyl,    -   (2) C₃₋₆ cycloalkyl,    -   (3) aryl,    -   (4) —S(O)₂-aryl, and    -   (5) heterocyclyl;    -   wherein the C₁₋₆ alkyl of (1) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b) C₃₋₆        cycloalkyl, (c) —O—C₁₋₆ alkyl, and (d) heterocyclyl; and    -   wherein each of the C₃₋₆ cycloalkyl of (2), aryl of (3) and (4),        and heterocyclyl of (5) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —CN, (c) —O—C₁₋₆ alkyl, and (d) C₁₋₆ alkyl optionally        substituted with 1-3 halogens;        R³ is selected from:    -   (1) H,    -   (2) halogen,    -   (3) C₁₋₆ alkyl, optionally substituted with —OH, and    -   (4) —C═N—C₁₋₆ alkyl; and        each of R⁴ and R⁵ is independently selected from:    -   (1) H,    -   (2) halogen,    -   (3) C₁₋₆ alkyl,    -   (4) —OH, and    -   (5) —O—C₁₋₆ alkyl.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

L is selected from (1) —NHC(O)— and (2) —C(O)NH—; and

R³ is selected from (1) H, (2) halogen, (3) C₁₋₄ alkyl, optionallysubstituted with —OH, and (4) —C═N—C₁₋₄ alkyl.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

R³ is selected from (1) H, (2) fluoro, (3) methyl, (4) ethyl, (5)—CH₃—OH, and (6) —C═N—C(CH₃)₃.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

each of R⁴ and R⁵ is independently selected from (1) H, (2) halogen, (3)methyl, and (4) —OH.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

R¹ is selected from:

-   -   (1) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —O—C₁₋₆ alkyl, and (c) C₁₋₆ alkyl optionally substituted with        1-3 halogens,    -   (2) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c) —O—C₁₋₆        alkyl, and (d) C₁₋₆ alkyl optionally substituted with 1-3        substituents independently selected from (a) halogen and (b)        —NH₂,    -   (3) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, wherein the bicyclic ring is optionally        substituted with halogen or C₁₋₆ alkyl, and    -   (4) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, (c) an aromatic 4-7 membered        monocyclic heterocyclyl, and (d) a 6-9 membered fused bicyclic        ring containing one or more heteroatoms selected from N, O, and        S in either of the rings, wherein the heterocyclyl is optionally        substituted with 1-3 substituents independently selected        from (a) halogen and (b) C₁₋₆ alkyl, optionally substituted with        1-3 halogens.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

R¹ is selected from:

-   -   (1) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        methyl, (c) ethyl, (d) —CHF₂, and (e) —CF₃,    -   (2) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c)        methyl, (d) ethyl, (e) —CHF₂, (f) —CF₃, and (g) —CH₂NH₂, (3) a        bicyclic ring comprising a phenyl fused to a cyclobutyl,        optionally substituted with halogen or C₁₋₆ alkyl and    -   (4) a heterocyclyl selected from azetidinyl,        imidazole-[1,2-b]pyridazinyl, isoxazolyl, isothiazolyl,        oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl,        tetrahydropyranyl, and 1,2,3-thiadiazolyl, wherein each        heterocyclyl is optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) methyl, and (c)        ethyl.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

R² is selected from:

-   -   (1) C₁₋₆ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —O—C₁₋₆ alkyl,        and (c) C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —O—C₁₋₆ alkyl, and (c) C₁₋₆ alkyl optionally substituted with        1-3 substituents independently selected from (a) fluoro and (b)        —NH₂,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, and (c) C₁₋₆        alkyl,    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆        alkyl,    -   (5) —S(O)₂-aryl, and    -   (6) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, and (c) an aromatic 4-7        membered monocyclic heterocyclyl, wherein each heterocyclyl is        optionally substituted with 1-3 substituents independently        selected from (a) halogen and (b) C₁₋₆ alkyl, optionally        substituted with 1-3 halogens.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

R² is selected from:

-   -   (1) C₁₋₄ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —O—C₁₋₄ alkyl,        and (c) C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        methyl, (c) ethyl, (d) —CH₃—NH₂, (e) CHF₂, (f) CF₃, and (g)        —O-ethyl,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) methyl, (c) ethyl,        and (d) —CN,    -   (4) —S(O)₂-phenyl, and    -   (5) a heterocyclyl selected from azetidinyl, imidazolyl,        oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl,        tetrahydrofuranyl, tetrahydropyranyl, and thiazolyl, wherein        each heterocyclyl is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        methyl, (c) ethyl, and (c) —CH₂CF₃.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

W is selected from (1) —C(O)NH— and (2) —NHC(O)—;

R¹ is selected from:

-   -   (1) C₁₋₆ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) C₃₋₆ cycloalkyl        and (c) —O—C₁₋₆ alkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —O—C₁₋₆ alkyl and (c) C₁₋₆ alkyl optionally substituted with 1-3        halogens,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c) —O—C₁₋₆        alkyl and (d) C₁₋₆ alkyl optionally substituted with 1-3        substituents independently selected from (i) halogen and (ii)        —NH₂,    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, wherein the bicyclic ring is optionally        substituted with halogen or C₁₋₆ alkyl, and    -   (5) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, (c) an aromatic 4-7 membered        monocyclic heterocyclyl, and (d) a 6-9 membered fused bicyclic        ring containing one or more heteroatoms selected from N, O, and        S in either of the rings, wherein the heterocyclyl is optionally        substituted with 1-3 substituents independently selected        from (a) halogen and (b) C₁₋₆ alkyl, optionally substituted with        1-3 halogens;

R² is selected from:

-   -   (1) C₁₋₆ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —O—C₁₋₄alkyl,        and (c) C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen and (b)        C₁₋₆ alkyl optionally substituted with 1-3 substituents        independently selected from (i) halogen, (ii) —O—C₁₋₄alkyl,        and (iii) —NH₂,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, and (b) C₁₋₆        alkyl,    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆        alkyl,    -   (5) —S(O)₂-phenyl, and    -   (6) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, and (c) an aromatic 4-7        membered monocyclic heterocyclyl, wherein the heterocyclyl is        optionally substituted with 1-3 substituents independently        selected from (a) halogen and (b) C₁₋₆ alkyl optionally        substituted with 1-3 halogens;        R³ is selected from (1) H, (2) halogen, (3) C₁₋₄ alkyl,        optionally substituted with —OH, and (4) —C═N—C₁₋₄ alkyl; and        each of R⁴ and R⁵ is independently selected from (1) H, (2)        halogen, (3) —OH, and (4) methyl.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, the compound is of formula (Ia):

wherein R¹ is selected from:

-   -   (1) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents halogens,    -   (2) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, and (c) C₁₋₆        alkyl optionally substituted with 1-3 substituents independently        selected from (a) halogen and (b) —NH₂,    -   (3) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, wherein the bicyclic ring is optionally        substituted with halogen or C₁₋₆ alkyl, and    -   (4) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, (c) an aromatic 4-7 membered        monocyclic heterocyclyl, and (d) a 6-9 membered fused bicyclic        ring containing one or more heteroatoms selected from N, O, and        S in either of the rings, wherein the heterocyclyl is optionally        substituted with 1-3 substituents independently selected        from (a) halogen and (b) C₁₋₆ alkyl, optionally substituted with        1-3 halogens;        R² is selected from:    -   (1) C₁₋₆ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen and (b)        C₁₋₆ alkyl optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —O—C₁₋₄ alkyl,        and (c) —NH₂,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, and (c) C₁₋₆        alkyl,    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆        alkyl,    -   (5) —S(O)₂-aryl, and    -   (6) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, and (c) an aromatic 4-7        membered monocyclic heterocyclyl, wherein the heterocyclyl is        optionally substituted with 1-3 substituents independently        selected from (a) halogen and (b) C₁₋₆ alkyl, optionally        substituted with 1-3 halogens;        R³ is selected from (1) H, (2) fluoro, (3) methyl, (4)        ethyl, (5) —CH₂—OH, and (6) —C═N—C(CH₃)₃;

and

each of R⁴ and R⁵ is independently selected from (1) H, (2) halogen, (3)—OH, and (4) methyl.

In one embodiment of the compound of formula (Ia), or a pharmaceuticallyacceptable salt thereof:

R¹ is selected from:

(1) C₃₋₆ cycloalkyl, optionally substituted with 1-3 halogens,

(2) phenyl, optionally substituted with 1-3 substituents independentlyselected from (a) halogen, (b) —CN, (c) methyl, (d) —CH₂NH₂,

(3) a bicyclic ring comprising a phenyl fused to a cyclobutyl, and

(4) a heterocyclyl selected from azetidinyl, imidazo[1,2-b]pyridazinyl,oxazolyl, pyridinyl, pyrimidinyl, tetrahydropyranyl, and1,2,3-thiadiazolyl, wherein the heterocyclyl is optionally substitutedwith 1-3 halogens;

R² is selected from:

-   -   (1) C₁₋₄ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —O—C₁₋₄ alkyl, and        C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        methyl, (c) ethyl, (d) —O-ethyl, (e) —CHF₂, and (f) —CF₃,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) —CN,    -   (4) a bicyclic ring comprising a phenyl fused to a cyclobutyl,        optionally substituted with 1-3 halogens,    -   (5) —S(O)₂-phenyl, and    -   (6) a heterocyclyl selected from azetidinyl, imidazolyl,        oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl,        tetrahydrofuranyl, tetrahydropyranyl and thiazolyl, wherein the        heterocyclyl is optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) methyl, (c) ethyl,        and (d) —CH₂CF₃;        R³ is selected from (1) H, (2) fluoro, (3) methyl, (4) —CH₃—OH,        and (5) —C═N—C(CH₃)₃; and each of R⁴ and R⁵ is independently        selected from (1) H, (2) fluoro, and (3) —OH.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, the compound is of formula (Ib):

wherein:R¹ is selected from:

-   -   (1) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —O—C₁₋₆ alkyl and (c) C₁₋₆ alkyl optionally substituted with 1-3        halogens,    -   (2) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c) —O—C₁₋₆        alkyl and (d) C₁₋₆ alkyl optionally substituted with 1-3        halogens,    -   (3) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, wherein the bicyclic ring is optionally        substituted with halogen or C₁₋₆ alkyl, and    -   (4) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, (c) an aromatic 4-7 membered        monocyclic heterocyclyl, and (d) a 6-9 membered fused bicyclic        ring containing one or more heteroatoms selected from N, O, and        S in either of the rings, wherein the heterocyclyl is optionally        substituted with 1-3 substituents independently selected        from (a) halogen, (b) —CN and (c) C₁₋₆ alkyl;        R² is selected from:    -   (1) C₁₋₆ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen and (b)        C₁₋₆ alkyl optionally substituted with —NH₂,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₁₋₆ alkyl,    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆        alkyl,    -   (5) —S(O)₂-aryl, and    -   (6) a heterocyclyl selected from (a) a saturated 4-7 membered        monocyclic heterocyclyl, (b) a partially unsaturated 4-7        membered monocyclic heterocyclyl, and (c) an aromatic 4-7        membered monocyclic heterocyclyl, wherein the heterocyclyl is        optionally substituted with 1-3 substituents independently        selected from (a) halogen and (b) C₁₋₆ alkyl;        R³ is selected from (1) H, (2) fluoro, (3) methyl, (4)        ethyl, (5) —CH₃—OH, and (6) —C═N—C(CH₃)₃;

and

each of R⁴ and R⁵ is independently selected from (1) H, (2) halogen, (3)—OH, and (4) methyl.

In one embodiment of the compound of formula (Ib), or a pharmaceuticallyacceptable salt thereof:

R¹ is selected from:

-   -   (1) C₃₋₆ cycloalkyl, optionally substituted with 1-3 halogens,    -   (2) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c)        methyl, (d) —CH₂NH₂,    -   (3) a bicyclic ring comprising a phenyl fused to a cyclobutyl,        and    -   (4) a heterocyclyl selected from azetidinyl,        imidazo[1,2-b]pyridazinyl, oxazolyl, pyridinyl, pyrimidinyl,        tetrahydropyranyl, and 1,2,3-thiadiazolyl, wherein the        heterocyclyl is optionally substituted with 1-3 halogens;        R² is selected from:    -   (1) C₁₋₄ alkyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —O—C₁₋₄ alkyl, and        C₃₋₆ cycloalkyl,    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        methyl, (c) ethyl, (d) —O-ethyl, (e) —CHF₂, and (f) —CF₃,    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) —CN,    -   (4) a bicyclic ring comprising a phenyl fused to a cyclobutyl,        optionally substituted with 1-3 halogens,    -   (5) —S(O)₂-phenyl, and    -   (6) a heterocyclyl selected from azetidinyl, imidazolyl,        oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl,        tetrahydrofuranyl, tetrahydropyranyl and thiazolyl, wherein the        heterocyclyl is optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) methyl, (c) ethyl,        and (d) —CH₂CF₃;        R³ is selected from (1) H, (2) fluoro, (3) methyl, (4) —CH₃—OH,        and (5) —C═N—C(CH₃)₃; and each of R⁴ and R⁵ is independently        selected from (1) H, (2) fluoro, and (3) —OH.

In one embodiment of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

L is selected from —NHC(O)— and —C(O)NH—;

W is selected from —C(O)NH— and —NHC(O)—;

R¹ is selected from:

-   -   (1) C₁₋₆alkyl,    -   (2) C₃₋₆ cycloalkyl,    -   (3) aryl and    -   (4) heterocyclyl;    -   wherein the C₁₋₆ alkyl of (1) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b) C₃₋₆        cycloalkyl and (c) —O—C₁₋₆ alkyl; and    -   wherein each of the C₃₋₆ cycloalkyl of (2), aryl of (3) and        heterocyclyl of (4) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b) C₃₋₆        cycloalkyl, (c) —CN, (d) —O—C₁₋₆ alkyl and (e) C₁₋₆ alkyl        optionally substituted with 1-3 substituents independently        selected from halogen and —NH₂;        R² is selected from:    -   (1) C₁₋₆alkyl,    -   (2) C₃₋₆ cycloalkyl,    -   (3) aryl,    -   (4) —S(O)₂-aryl and    -   (5) heterocyclyl;    -   wherein the C₁₋₆ alkyl of (1) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b) C₃₋₆        cycloalkyl, (c) —O—C₁₋₆ alkyl and (d) heterocyclyl; and    -   wherein each of the C₃₋₆ cycloalkyl of (2), aryl of (3) and (4)        and heterocyclyl of (5) is optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —CN, (c) —O—C₁₋₆ alkyl and (d) C₁₋₆ alkyl optionally substituted        with 1-3 halogens;        R³ is selected from H, halogen, C₁₋₆ alkyl and —C═N—C₁₋₆ alkyl;        and        each of R⁴ and R⁵ is independently selected from H, halogen,        C₁₋₆ alkyl, —OH and —O—C₁₋₆ alkyl.

In one embodiment of the compound of formula (Ia), or a pharmaceuticallyacceptable salt thereof:

R¹ is selected from:

-   -   (1) C₁₋₆ alkyl; optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) C₃₋₆ cycloalkyl        and (c) —O—C₁₋₆ alkyl;    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —O—C₁₋₆ alkyl and (c) C₁₋₆ alkyl optionally substituted with 1-3        halogens;    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c) —O—C₁₋₆        alkyl and (d) C₁₋₆ alkyl optionally substituted with 1-3        halogens;    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, wherein the bicyclic ring is optionally        substituted with halogen or C₁₋₆ alkyl; and    -   (5) a heterocyclyl selected from a saturated, a partially        unsaturated and an aromatic 4-7 membered monocyclic heterocyclyl        and a fused bicyclic ring containing one or more heteroatoms        selected from N, O, and S in either of the rings; wherein the        heterocyclyl is optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN and (c) C₁₋₆        alkyl;        R² is selected from:    -   (1) C₁₋₆ alkyl; optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₃₋₆ cycloalkyl;    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen and (b)        C₁₋₆ alkyl optionally substituted with —NH₂;    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₁₋₆ alkyl;    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆        alkyl; and    -   (5) a heterocyclyl selected from a saturated, a partially        unsaturated and an aromatic 4-7 membered monocyclic        heterocyclyl; wherein the heterocyclyl is optionally substituted        with 1-3 substituents independently selected from (a)        halogen, (b) —CN and (c) C₁₋₆ alkyl;        R³ is selected from H and halogen; and        each of R⁴ and R⁵ is independently selected from H, halogen, —OH        and methyl.

In one embodiment of the compound of formula (Ib), or a pharmaceuticallyacceptable salt thereof:

R¹ is selected from:

-   -   (1) C₁₋₆ alkyl; optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) C₃₋₆ cycloalkyl        and (c) —O—C₁₋₆ alkyl;    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen, (b)        —O—C₁₋₆ alkyl and (c) C₁₋₆ alkyl optionally substituted with 1-3        halogens;    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN, (c) —O—C₁₋₆        alkyl and (d) C₁₋₆ alkyl optionally substituted with 1-3        halogens;    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, wherein the bicyclic ring is optionally        substituted with halogen or C₁₋₆ alkyl; and    -   (5) a heterocyclyl selected from a saturated, a partially        unsaturated and an aromatic 4-7 membered monocyclic heterocyclyl        and a fused bicyclic ring containing one or more heteroatoms        selected from N, O, and S in either of the rings; wherein the        heterocyclyl is optionally substituted with 1-3 substituents        independently selected from (a) halogen, (b) —CN and (c) C₁₋₆        alkyl;        R² is selected from:    -   (1) C₁₋₆ alkyl; optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₃₋₆ cycloalkyl;    -   (2) C₃₋₆ cycloalkyl, optionally substituted with 1-3        substituents independently selected from (a) halogen and (b)        C₁₋₆ alkyl optionally substituted with —NH₂;    -   (3) phenyl, optionally substituted with 1-3 substituents        independently selected from (a) halogen and (b) C₁₋₆ alkyl;    -   (4) a bicyclic ring comprising a phenyl fused to a        C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆        alkyl; and    -   (5) a heterocyclyl selected from a saturated, a partially        unsaturated and an aromatic 4-7 membered monocyclic        heterocyclyl; wherein the heterocyclyl is optionally substituted        with 1-3 substituents independently selected from (a)        halogen, (b) —CN and (c) C₁₋₆ alkyl;        R³ is selected from H and halogen; and        each of R⁴ and R⁵ is independently selected from H, halogen, —OH        and methyl.

In one embodiment, a compound disclosed herein is selected from thegroup consisting of the compounds exemplified in Examples 1 to 88; or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a pharmaceutical composition comprising acompound disclosed herein and at least one pharmaceutically acceptablecarrier.

Also disclosed herein is a method of inhibiting activity of indoleamine2,3-dioxygenase (IDO) comprising contacting IDO with a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof.

Also disclosed herein is a method of inhibiting immunosuppression in apatient comprising administering to said patient an effective amount ofa compound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

Also disclosed herein is a method of treating cancer, viral infection,depression, a neurodegenerative disorder, trauma, age-related cataracts,organ transplant rejection, or an autoimmune disease in a patientcomprising administering to said patient an effective amount of acompound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

Also disclosed herein is a method of treating melanoma in a patientcomprising administering to said patient an effective amount of acompound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

Further disclosed herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in therapy. In oneembodiment, disclosed herein is the use of a compound disclosed herein,or a pharmaceutically acceptable salt, solvate or hydrate thereof, forthe preparation of a medicament for use in therapy.

“Alkyl” refers to both branched- and straight-chain saturated aliphatichydrocarbon groups of 1 to 18 carbon atoms, or more specifically, 1 to12 carbon atoms. Examples of such groups include, but are not limitedto, methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl,n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl(i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentyl, and isohexyl.Alkyl groups may be optionally substituted with one or more substituentsas defined herein. “C₁₋₆alkyl” refers to an alkyl group as definedherein having 1 to 6 carbon atoms.

“Aryl” refers to an aromatic monocyclic or multicyclic ring moietycomprising 6 to 14 ring carbon atoms, or more specifically, 6 to 10 ringcarbon atoms. Monocyclic aryl rings include, but are not limited to,phenyl. Multicyclic rings include, but are not limited to, naphthyl andbicyclic rings wherein phenyl is fused to a C₄₋₇cycloalkyl orC₄₋₇cycloalkenyl ring. Aryl groups may be optionally substituted withone or more substituents as defined herein. Bonding can be through anyof the carbon atoms of any ring.

In one embodiment, the aryl is phenyl. In another embodiment, the arylis a bicyclic ring wherein phenyl is fused to a 4-7 membered cycloalkylring. In another embodiment, the aryl is a bicyclic ring wherein phenylis fused to a 4-membered cycloalkyl ring. In another embodiment, thearyl is a bicyclic ring wherein phenyl is fused to a 4-memberedcycloalkenyl ring. In another embodiment, the aryl isbicyclo[4.2.0]octa-1(6),2,4-trienyl.

“Cycloalkyl” refers to a monocyclic saturated carbocyclic ring havingthe specified number of carbon atoms. For example, C₃₋₆cycloalkyl refersto a cycloalkyl group as defined herein having 3 to 6 carbon atoms.Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptanyl. Cycloalkyl groupsmay be optionally substituted with one or more substituents as definedherein. In one embodiment, the cycloalkyl is a 5-membered bridgedbicyclic ring.

“Halo” or “halogen” refers to fluoro, chloro, bromo or iodo, unlessotherwise noted.

“Heterocycle” or “heterocyclyl” refers to a saturated, partiallyunsaturated or aromatic ring moiety having at least one ring heteroatomand at least one ring carbon atom. In one embodiment, the heteroatom isoxygen, sulfur, or nitrogen. A heterocycle containing more than oneheteroatom may contain different heteroatoms. Heterocyclyl moietiesinclude both monocyclic and multicyclic (e.g., bicyclic) ring moieties.Bicyclic ring moieties include fused, spirocycle and bridged bicyclicrings and may comprise one or more heteroatoms in either of the rings.The ring attached to the remainder of the molecule may or may notcontain a heteroatom. Either ring of a bicyclic heterocycle may besaturated, partially unsaturated or aromatic. The heterocycle may beattached to the rest of the molecule via a ring carbon atom, a ringoxygen atom or a ring nitrogen atom. Non-limiting examples ofheterocycles are described below.

In one embodiment, the heterocyclyl is selected from azetidinyl,dioxanyl, imidazolyl, imidazo[1,2-b]pyridazinyl, oxazolyl, pyrazinyl,pyrazolyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl,1,2,3-thiadizolyl, and thiazolyl.

In one embodiment, the heterocyclyl is selected from azetidinyl,imidazo[1,2-b]pyridazinyl, oxazolyl, pyridinyl, pyrimidinyl,tetrahydropyranyl, and 1,2,3-thiadizolyl.

In one embodiment, the heterocyclyl is selected from azetidinyl,dioxanyl, imidazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl,pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl and thiazolyl.

Heterocyclic groups may be optionally substituted with one or moresubstituents as defined herein.

“Optionally substituted” refers to “unsubstituted or substituted,” andtherefore, the generic structural formulas described herein encompasscompounds containing the specified optional substituent(s) as well ascompounds that do not contain the optional substituent(s). Eachsubstituent is independently defined each time it occurs within thegeneric structural formula definitions.

Polymorphism

A compound disclosed herein, including a salt, solvate or hydratethereof, may exist in crystalline form, non-crystalline form, or amixture thereof. A compound or a salt or solvate thereof may alsoexhibit polymorphism, i.e. the capacity of occurring in differentcrystalline forms. These different crystalline forms are typically knownas “polymorphs”. Polymorphs have the same chemical composition butdiffer in packing, geometrical arrangement, and other descriptiveproperties of crystalline solid state. Polymorphs, therefore, may havedifferent physical properties such as shape, density, hardness,deformability, stability, and dissolution properties. Polymorphstypically exhibit different melting points, IR spectra, and X-ray powderdiffraction patterns, all of which may be used for identification. Oneof ordinary skill in the art will appreciate that different polymorphsmay be produced, for example, by changing or adjusting the conditionsused in crystallizing/recrystallizing a compound disclosed herein.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Included herein are various isomers of the compounds disclosed herein.The term “isomers” refers to compounds that have the same compositionand molecular weight but differ in physical and/or chemical properties.The structural difference may be in constitution (geometric isomers) orin the ability to rotate the plane of polarized light (stereoisomers).

With regard to stereoisomers, a compound disclosed herein may have oneor more asymmetric carbon atom and may occur as mixtures (such as aracemic mixture) or as individual enantiomers or diastereomers. All suchisomeric forms are included herein, including mixtures thereof. If acompound disclosed herein contains a double bond, the substituent may bein the E or Z configuration. If a compound disclosed herein contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon) of a compound disclosed herein, canbe present in racemic mixture or enantiomerically enriched, for examplethe (R)-, (S)- or (R,S)-configuration. In certain embodiments, eachasymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated double bondsmay, if possible, be present in cis- (Z)- or trans-(E)-form.

A compound disclosed herein, can be in the form of one of the possibleisomers, rotamers, atropisomers, tautomers or mixtures thereof, forexample, as substantially pure geometric (cis or trans) isomers,diastereomers, optical isomers (antipodes), racemates or mixturesthereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of the final compounds of the examples orintermediates can be resolved into the optical antipodes by knownmethods, e.g., by separation of the diastereomeric salts thereof,obtained with an optically active acid or base, and liberating theoptically active acidic or basic compound. In particular, a basic moietymay thus be employed to resolve the compounds of the present inventioninto their optical antipodes, e.g., by fractional crystallization of asalt formed with an optically active acid, e.g., tartaric acid,dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.Racemic compounds can also be resolved by chiral chromatography, e.g.,high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. For example,compounds including carbonyl —CH₂C(O)— groups (keto forms) may undergotautomerism to form hydroxyl —CH═C(OH)— groups (enol forms). Both ketoand enol forms, individually as well as mixtures thereof, are includedwithin the scope of the present invention.

Isotopic Variations

Compounds disclosed herein, include unlabeled forms, as well asisotopically labeled forms. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compoundsdisclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine, iodine and chlorine, such as ²H (i.e.,Deuterium or “D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³⁵S,¹⁸F, ¹²³I, ¹²⁵I and ³⁶Cl. The invention includes various isotopicallylabeled compounds as defined herein, for example those into whichradioactive isotopes, such as ³H and ¹⁴C, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labeled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, substitution with positron emitting isotopes,such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N may be particularly desirable for PET orSPECT studies.

Isotopically-labeled compounds disclosed herein, can generally beprepared by conventional techniques known to those skilled in the art.Furthermore, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index.

Pharmaceutically Acceptable Salts

The term “pharmaceutically acceptable salt” refers to a salt preparedfrom a pharmaceutically acceptable non-toxic base or acid, includinginorganic or organic base and inorganic or organic acid. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includeammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When a compound disclosed herein is basic, a salt may be prepared from apharmaceutically acceptable non-toxic acid, including an inorganic andorganic acid. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroaceticacid (TFA) and the like. Particular embodiments include the citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric,tartaric and trifluoroacetic acids.

Methods of Use

Compounds disclosed herein can inhibit activity of the enzymeindoleamine-2,3-dioxygenase (IDO). For example, the compounds disclosedherein can potentially be used to inhibit activity of IDO in cell or inan individual in need of modulation of the enzyme by administering aneffective amount of a compound. Further disclosed herein are methods ofinhibiting the degradation of tryptophan in a system containing cellsexpressing IDO such as a tissue, living organism, or cell culture. Insome embodiments, the present invention provides methods of altering(e.g., increasing) extracellular tryptophan levels in a mammal byadministering an effective amount of a compound or composition providedherein. Methods of measuring tryptophan levels and tryptophandegradation are routine in the art.

Also disclosed herein are methods of inhibiting immunosuppression suchas IDO-mediated immunosuppression in a patient by administering to thepatient an effective amount of a compound or composition recited herein.IDO-mediated immunosuppression has been associated with, for example,cancers, tumor growth, metastasis, viral infection, viral replication,etc.

Also disclosed herein are methods of treating diseases associated withactivity or expression, including abnormal activity and/oroverexpression, of IDO in an individual (e.g., patient) by administeringto the individual in need of such treatment an effective amount or doseof a compound disclosed herein or a pharmaceutical composition thereof.Example diseases can include any disease, disorder or condition that maybe directly or indirectly linked to expression or activity of the IDOenzyme, such as over expression or abnormal activity. An IDO-associateddisease can also include any disease, disorder or condition that may beprevented, ameliorated, or cured by modulating enzyme activity. Examplesof IDO-associated diseases include cancer, viral infection such as HIVand HCV, depression, neurodegenerative disorders such as Alzheimer'sdisease and Huntington's disease, trauma, age-related cataracts, organtransplantation (e.g., organ transplant rejection), and autoimmunediseases including asthma, rheumatoid arthritis, multiple sclerosis,allergic inflammation, inflammatory bowel disease, psoriasis andsystemic lupus erythematosusor. Example cancers potentially treatable bythe methods herein include cancer of the colon, pancreas, breast,prostate, lung, brain, ovary, cervix, testes, renal, head and neck,lymphoma, leukemia, melanoma, and the like. The compounds of theinvention may also be useful in the treatment of obesity and ischemia.As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the IDO enzyme with a compound disclosed hereinincludes the administration of a compound of the present invention to anindividual or patient, such as a human, as well as, for example,introducing a compound of the invention into a sample containing acellular or purified preparation containing the IDO enzyme.

A subject administered with a compound disclosed herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, isgenerally a mammal, such as a human being, male or female. A subjectalso refers to cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, and birds. In one embodiment, the subject is a human.

As used herein, the terms “treatment” and “treating” refer to allprocesses wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of a disease or disorderthat may be associated with IDO enzyme activity. The terms do notnecessarily indicate a total elimination of all disease or disordersymptoms. The terms also include the potential prophylactic therapy ofthe mentioned conditions, particularly in a subject that is predisposedto such disease or disorder.

The terms “administration of” and or “administering a” compound shouldbe understood to include providing a compound described herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, andcompositions of the foregoing to a subject.

The amount of a compound administered to a subject is an amountsufficient to inhibit IDO enzyme activity in the subject. In anembodiment, the amount of a compound can be an “effective amount”,wherein the subject compound is administered in an amount that willelicit a biological or medical response of a tissue, system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician. An effective amount does not necessarily includeconsiderations of toxicity and safety related to the administration of acompound. It is recognized that one skilled in the art may affectphysiological disorders associated with an IDO enzyme activity bytreating a subject presently afflicted with the disorders, or byprophylactically treating a subject likely to be afflicted with thedisorders, with an effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, solvate or hydrate thereof.

An effective amount of a compound will vary with the particular compoundchosen (e.g. considering the potency, efficacy, and/or half-life of thecompound); the route of administration chosen; the condition beingtreated; the severity of the condition being treated; the age, size,weight, and physical condition of the subject being treated; the medicalhistory of the subject being treated; the duration of the treatment; thenature of a concurrent therapy; the desired therapeutic effect; and likefactors and can be routinely determined by the skilled artisan.

The compounds disclosed herein may be administered by any suitable routeincluding oral and parenteral administration. Parenteral administrationis typically by injection or infusion and includes intravenous,intramuscular, and subcutaneous injection or infusion.

The compounds disclosed herein may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound disclosed herein depend on the pharmacokineticproperties of that compound, such as absorption, distribution andhalf-life which can be determined by a skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound disclosed herein depend on the disease orcondition being treated, the severity of the disease or condition, theage and physical condition of the subject being treated, the medicalhistory of the subject being treated, the nature of concurrent therapy,the desired therapeutic effect, and like factors within the knowledgeand expertise of the skilled artisan. It will be further understood bysuch skilled artisans that suitable dosing regimens may requireadjustment given an individual subject's response to the dosing regimenor over time as the individual subject needs change. Typical dailydosages may vary depending upon the particular route of administrationchosen. Typical daily dosages for oral administration, to a humanweighing approximately 70 kg would range from about 0.1 mg to about 2grams, or more specifically, 0.1 mg to 500 mg, or even morespecifically, 0.2 mg to 100 mg, of a compound disclosed herein.

One embodiment of the present invention provides for a method oftreating a disease or disorder associated with IDO enzyme activitycomprising administration of an effective amount of a compound disclosedherein to a subject in need of treatment thereof. In one embodiment, thedisease or disorder associated with an IDO enzyme is a cellproliferation disorder.

In one embodiment, disclosed herein is the use of a compound disclosedherein in a therapy. The compound may be useful in a method ofinhibiting IDO enzyme activity in a subject, such as a mammal in need ofsuch inhibition, comprising administering an effective amount of thecompound to the subject.

In one embodiment, disclosed herein is a pharmaceutical compositioncomprising a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate or hydrate thereof, for use in potential treatment of adisorder or disease related to IDO enzyme activity.

Compositions

The term “composition” as used herein is intended to encompass a dosageform comprising a specified compound in a specified amount, as well asany dosage form which results, directly or indirectly, from combinationof a specified compound in a specified amount. Such term is intended toencompass a dosage form comprising a compound disclosed herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, and one ormore pharmaceutically acceptable carriers or excipients. Accordingly,the compositions of the present invention encompass any composition madeby admixing a compound of the present invention and one or morepharmaceutically acceptable carrier or excipients. By “pharmaceuticallyacceptable” it is meant the carriers or excipients are compatible withthe compound disclosed herein and with other ingredients of thecomposition.

In one embodiment, disclosed herein is a composition comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof, and one or more pharmaceutically acceptablecarriers or excipients. The composition may be prepared and packaged inbulk form wherein an effective amount of a compound of the invention canbe extracted and then given to a subject, such as with powders orsyrups. Alternatively, the composition may be prepared and packaged inunit dosage form wherein each physically discrete unit contains aneffective amount of a compound disclosed herein. When prepared in unitdosage form, the composition of the invention typically contains fromabout 0.1 mg to 2 grams, or more specifically, 0.1 mg to 500 mg, or evenmore specifically, 0.2 mg to 100 mg, of a compound disclosed herein, ora pharmaceutically acceptable salt, solvate or hydrate thereof.

A compound disclosed herein and a pharmaceutically acceptable carrier orexcipient(s) will typically be formulated into a dosage form adapted foradministration to a subject by a desired route of administration. Forexample, dosage forms include those adapted for (1) oral administration,such as tablets, capsules, caplets, pills, troches, powders, syrups,elixirs, suspensions, solutions, emulsions, sachets, and cachets; and(2) parenteral administration, such as sterile solutions, suspensions,and powders for reconstitution. Suitable pharmaceutically acceptablecarriers or excipients will vary depending upon the particular dosageform chosen. In addition, suitable pharmaceutically acceptable carriersor excipients may be chosen for a particular function that they mayserve in the composition. For example, certain pharmaceuticallyacceptable carriers or excipients may be chosen for their ability tofacilitate the production of uniform dosage forms. Certainpharmaceutically acceptable carriers or excipients may be chosen fortheir ability to facilitate the production of stable dosage forms.Certain pharmaceutically acceptable carriers or excipients may be chosenfor their ability to facilitate the carrying or transporting of acompound disclosed herein, once administered to the subject, from oneorgan or portion of the body to another organ or another portion of thebody. Certain pharmaceutically acceptable carriers or excipients may bechosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, lubricants, binders, disintegrants,fillers, glidants, granulating agents, coating agents, wetting agents,solvents, co-solvents, suspending agents, emulsifiers, sweeteners,flavoring agents, flavor masking agents, coloring agents, anti-cakingagents, hemectants, chelating agents, plasticizers, viscosity increasingagents, antioxidants, preservatives, stabilizers, surfactants, andbuffering agents.

A skilled artisan possesses the knowledge and skill in the art to selectsuitable pharmaceutically acceptable carriers and excipients inappropriate amounts for the use in the invention. In addition, there area number of resources available to the skilled artisan, which describepharmaceutically acceptable carriers and excipients and may be useful inselecting suitable pharmaceutically acceptable carriers and excipients.Examples include Remington's Pharmaceutical Sciences (Mack PublishingCompany), The Handbook of Pharmaceutical Additives (Gower PublishingLimited), and The Handbook of Pharmaceutical Excipients (the AmericanPharmaceutical Association and the Pharmaceutical Press).

The compositions of the invention are prepared using techniques andmethods known to those skilled in the art. Some methods commonly used inthe art are described in Remington's Pharmaceutical Sciences (MackPublishing Company).

In one embodiment, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising an effective amount of a compoundof the invention and a diluent or filler. Suitable diluents and fillersinclude lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.corn starch, potato starch, and pre-gelatinized starch), cellulose andits derivatives, (e.g. microcrystalline cellulose), calcium sulfate, anddibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch) gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds disclosed herein may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyrancopolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanacrylates and cross-linked oramphipathic block copolymers of hydrogels.

In one embodiment, the invention is directed to a liquid oral dosageform. Oral liquids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of a compound disclosed herein. Syrups can be prepared bydissolving the compound of the invention in a suitably flavored aqueoussolution; while elixirs are prepared through the use of a non-toxicalcoholic vehicle. Suspensions can be formulated by dispersing acompound disclosed herein in a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylenesorbitol ethers, preservatives, flavor additives such as peppermint oilor other natural sweeteners or saccharin or other artificial sweetenersand the like can also be added.

In one embodiment, the invention is directed to compositions forparenteral administration. Compositions adapted for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions which may contain anti-oxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Thecompositions may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets.

Combinations

A compound disclosed herein may be used in combination with one or moreother active agents, including but not limited to, other anti-canceragents, that are used in the prevention, treatment, control,amelioration, or reduction of risk of a particular disease or condition(e.g., cell proliferation disorders). In one embodiment, a compounddisclosed herein is combined with one or more other anti-cancer agentsfor use in the prevention, treatment, control amelioration, or reductionof risk of a particular disease or condition for which the compoundsdisclosed herein are useful. Such other active agents may beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention.

When a compound disclosed herein is used contemporaneously with one ormore other active agents, a composition containing such other activeagents in addition to the compound disclosed herein is contemplated.Accordingly, the compositions of the present invention include thosethat also contain one or more other active ingredients, in addition to acompound disclosed herein. A compound disclosed herein may beadministered either simultaneously with, or before or after, one or moreother therapeutic agent(s). A compound disclosed herein may beadministered separately, by the same or different route ofadministration, or together in the same pharmaceutical composition asthe other agent(s).

Products provided as a combined preparation include a compositioncomprising a compound disclosed herein and one or more other activeagent(s) together in the same pharmaceutical composition, or a compounddisclosed herein, and one or more other therapeutic agent(s) in separateform, e.g. in the form of a kit.

The weight ratio of a compound disclosed herein to a second active agentmay be varied and will depend upon the effective dose of each agent.Generally, an effective dose of each will be used. Thus, for example,when a compound disclosed herein is combined with another agent, theweight ratio of the compound disclosed herein to the other agent willgenerally range from about 1000:1 to about 1:1000, such as about 200:1to about 1:200. Combinations of a compound disclosed herein and otheractive agents will generally also be within the aforementioned range,but in each case, an effective dose of each active agent should be used.In such combinations, the compound disclosed herein and other activeagents may be administered separately or in conjunction. In addition,the administration of one element may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

In one embodiment, the invention provides a composition comprising acompound disclosed herein, and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease ordisorder associated with IDO enzyme activity.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound disclosed herein. In one embodiment, the kit comprises meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

A kit disclosed herein may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist with compliance, akit of the invention typically comprises directions for administration.

Disclosed herein is a use of a compound disclosed herein, for treating adisease or disorder associated with IDO enzyme activity, wherein themedicament is prepared for administration with another active agent. Theinvention also provides the use of another active agent for treating adisease or disorder associated with an IDO enzyme, wherein themedicament is administered with a compound disclosed herein.

The invention also provides the use of a compound disclosed herein fortreating a disease or disorder associated with IDO enzyme activity,wherein the patient has previously (e.g. within 24 hours) been treatedwith another active agent. The invention also provides the use ofanother therapeutic agent for treating a disease or disorder associatedwith IDO enzyme activity, wherein the patient has previously (e.g.within 24 hours) been treated with a compound disclosed herein. Thesecond agent may be applied a week, several weeks, a month, or severalmonths after the administration of a compound disclosed herein.

In one embodiment, the other active agent is selected from the groupconsisting of vascular endothelial growth factor (VEGF) receptorinhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylatingagents, anti-tumor antibiotics, anti-metabolites, retinoids,immunomodulatory agents including but not limited to anti-cancervaccines, CTLA-4, LAG-3 and PD-1 antagonists.

Examples of vascular endothelial growth factor (VEGF) receptorinhibitors include, but are not limited to, bevacizumab (sold under thetrademark AVASTIN by Genentech/Roche), axitinib,(N-methyl-2-[[3-[([pound])-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indoi-6-yl)-2-[(4-pyridinyimethyj)amino]-3-pyfidinecarboxamide.and described in PCT Publication No. WO 02/068470), pasireotide (alsoknown as SO 230, and described in PCT Publication No. WO 02/010192), andsorafenib (sold under the tradename NEXAVAR).

Examples of topoisomerase II inhibitors, include but are not limited to,etoposide (also known as VP-16 and Etoposide phosphate, sold under thetradenames TOPOSAR, VEPESID and ETOPOPHOS), and teniposide (also knownas VM-26, sold under the tradename VUMON).

Examples of alkylating agents, include but are not limited to,5-azacytidine (sold under the trade name VIDAZA), decitabine (sold underthe trade name of DECOGEN), temozolomide (sold under the trade namesTEMODAR and TEMODAL by Schering-Plough/Merck), dactinomycin (also knownas actinomycin-D and sold under the tradename COSMEGEN), melphalan (alsoknown as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under thetradename ALKERAN), altretamine (also known as hexamethylmelamine (HMM),sold under the tradename HEXALEN), carmustine (sold under the tradenameBCNU), bendamustine (sold under the tradename TREANDA), busulfan (soldunder the tradenames BUSULFEX and MYLERAN), carboplatin (sold under thetradename PARAPLATIN), lomustine (also known as CCNU, sold under thetradename CeeNU), cisplatin (also known as CDDP, sold under thetradenames PLATINOL and PLATINOL-AQ), chlorambucil (sold under thetradename LEUKERAN), cyclophosphamide (sold under the tradenames CYTOXANand NEOSAR), dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, sold under the tradename DTIC-DOME), altretamine (alsoknown as hexamethylmelamine (HMM) sold under the tradename HEXALEN),ifosfamide (sold under the tradename IFEX), procarbazine (sold under thetradename MATULANE), mechlorethamine (also known as nitrogen mustard,mustine and mechloroethamine hydrochloride, sold under the tradenameMUSTARGEN), streptozocin (sold under the tradename ZANOSAR), thiotepa(also known as thiophosphoamide, TESPA and TSPA, and sold under thetradename THIOPLEX).

Examples of anti-tumor antibiotics include, but are not limited to,doxorubicin (sold under the tradenames ADRIAMYCIN and RUBEX), bleomycin(sold under the tradename LENOXANE), daunorubicin (also known asdauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride,sold under the tradename CERUBIDINE), daunorubicin liposomal(daunorubicin citrate liposome, sold under the tradename DAUNOXOME),mitoxantrone (also known as DHAD, sold under the tradename NOVANTRONE),epirubicin (sold under the tradename ELLENCE), idarubicin (sold underthe tradenames IDAMYCIN, IDAMYCIN PFS), and mitomycin C (sold under thetradename MUTAMYCIN).

Examples of anti-metabolites include, but are not limited to, claribine(2-chlorodeoxyadenosine, sold under the tradename LEUSTATIN),5-fluorouracil (sold under the tradename ADRUCIL), 6-thioguanine (soldunder the tradename PURINETHOL), pemetrexed (sold under the tradenameALIMTA), cytarabine (also known as arabinosylcytosine (Ara-C), soldunder the tradename CYTOSAR-U), cytarabine liposomal (also known asLiposomal Ara-C, sold under the tradename DEPOCYT), decitabine (soldunder the tradename DACOGEN), hydroxyurea (sold under the tradenamesHYDREA, DROXIA and MYLOCEL), fludarabine (sold under the tradenameFLUDARA), floxuridine (sold under the tradename FUDR), cladribine (alsoknown as 2-chlorodeoxyadenosine (2-CdA) sold under the tradenameLEUSTATIN), methotrexate (also known as amethopterin, methotrexatesodium (MTX), sold under the tradenames RHEUMATREX and TREXALL), andpentostatin (sold under the tradename NIPENT).

Examples of retinoids include, but are not limited to, alitretinoin(sold under the tradename PANRETIN), tretinoin (all-trans retinoic acid,also known as ATRA, sold under the tradename VESANOID), Isotretinoin(13-c/s-retinoic acid, sold under the tradenames ACCUTANE, AMNESTEEM,CLARAVIS, CLARUS, DECUTAN, ISOTANE, IZOTECH, ORATANE, ISOTRET, andSOTRET), and bexarotene (sold under the tradename TARGRETIN).

“PD-1 antagonist” means any chemical compound or biological moleculethat blocks binding of PD-L1 expressed on a cancer cell to PD-1expressed on an immune cell (T cell, B cell or NKT cell) and preferablyalso blocks binding of PD-L2 expressed on a cancer cell to theimmune-cell expressed PD-1. Alternative names or synonyms for PD-1 andits ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1,PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC,Btdc and CD273 for PD-L2. In any of the treatment method, medicamentsand uses of the present invention in which a human individual is beingtreated, the PD-1 antagonist blocks binding of human PD-L1 to humanPD-1, and preferably blocks binding of both human PD-L1 and PD-L2 tohuman PD-1. Human PD-1 amino acid sequences can be found in NCBI LocusNo.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be foundin NCBI Locus No.: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in any of the treatment method, medicaments anduses of the present invention include a monoclonal antibody (mAb), orantigen binding fragment thereof, which specifically binds to PD-1 orPD-L1, and preferably specifically binds to human PD-1 or human PD-L1.The mAb may be a human antibody, a humanized antibody or a chimericantibody, and may include a human constant region. In some embodimentsthe human constant region is selected from the group consisting of IgG1,IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, thehuman constant region is an IgG1 or IgG4 constant region. In someembodiments, the antigen binding fragment is selected from the groupconsisting of Fab, Fab′-SH, F(ab′)₂, scFv and Fv fragments. Examples ofPD-1 and PD-L1 antagonists include, but are not limited to,pembrolizumab (sold under the tradename KEYTRUDA), nivolumab (sold underthe tradename OPDIVO), AND atezolizumab (sold under the trade nameTECENTRIQ).

Examples of mAbs that bind to human PD-1, and useful in the treatmentmethod, medicaments and uses of the present invention, are described inU.S. Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,168,757,WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.

Examples of mAbs that bind to human PD-L1, and useful in the treatmentmethod, medicaments and uses of the present invention, are described inWO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796. Specificanti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatmentmethod, medicaments and uses of the present invention include MPDL3280A,BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises theheavy chain and light chain variable regions of SEQ ID NO:24 and SEQ IDNO:21, respectively, of WO2013/019906.

Other PD-1 antagonists useful in any of the treatment method,medicaments and uses of the present invention include an immunoadhesinthat specifically binds to PD-1 or PD-L1, and preferably specificallybinds to human PD-1 or human PD-L1, e.g., a fusion protein containingthe extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to aconstant region such as an Fc region of an immunoglobulin molecule.Examples of immunoadhesion molecules that specifically bind to PD-1 aredescribed in WO2010/027827 and WO2011/066342. Specific fusion proteinsuseful as the PD-1 antagonist in the treatment method, medicaments anduses of the present invention include AMP-224 (also known as B7-DCIg),which is a PD-L2-FC fusion protein and binds to human PD-1.

Examples of other cytotoxic agents include, but are not limited to,arsenic trioxide (sold under the tradename TRISENOX), asparaginase (alsoknown as L-asparaginase, and Erwinia L-asparaginase, sold under thetradenames ELSPAR and KIDROLASE).

EXPERIMENTAL

The following synthetic schemes and examples are intended to beillustrative only and not limiting in any way. Abbreviations used arethose conventional in the art or the following.

-   -   ACN acetonitrile    -   aq. Aqueous    -   Boc tert-butyloxycarbonyl    -   Boc₂O di-tert-butyl dicarbonate    -   Calc'd calculated    -   Celite diatomaceous earth used as a filtration medium    -   CO carbon monoxide    -   Cu(I)I copper(I) iodide    -   CV column volume    -   ° C. degree celsius    -   CPhos Pd G4        [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-methylamino-1,1′-biphenyl)]        palladium(II) methanesulfonate    -   CV column volume(s)    -   DAST (dimethylamino)sulfur trifluoride    -   DCM dichloromethane    -   DIEA N,N-diisopropylethylamine    -   DIPEA N,N-diisopropylethylamine    -   DMA dimethylamine    -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   DPPA diphenylphosphoryl azide    -   DPPF 1,1′-bis(diphenylphosphino)ferrocene    -   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   EI electron ionization    -   EMEM Eagle's minimal essential medium    -   Et ethyl    -   Et₂O diethyl ether    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   g gram    -   h hour(s)    -   HATU        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid-hexafluorophosphate    -   HCl hydrochloric acid    -   HPLC high pressure liquid chromatography    -   JackiePhos Pd G3        [(2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate    -   JohnPhos (2-biphenyl)di-tert-butylphosphine    -   K₃PO₄ potassium phosphate tribasic    -   kg kilogram    -   KO′Bu potassium tert-butoxide    -   L liter    -   LC liquid chromatography    -   LCMS liquid chromatography and mass spectrometry    -   LiHMDS lithium bis(trimethylsilyl)amide    -   LiOH lithium hydroxide    -   M molar    -   Me methyl    -   MeOH methanol    -   mg miligram    -   mmol milimole    -   MS mass spectrometry    -   MTBE methyl tert-butyl ether    -   min minutes    -   mL milliliter(s)    -   m/z mass to charge ratio    -   nm nanometer    -   nM nanomolar    -   N normal    -   N₂ nitrogen    -   Na₂SO₄ sodium sulfate    -   NaH sodium hydride    -   NaHCO₃ sodium bicarbonate    -   NaHMDS sodium bis(trimethylsilyl)amide    -   NaN₃ sodium azide    -   NaOH sodium Hydroxide    -   NBS N-bromosuccinimide    -   NH₄Cl ammonium chloride    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)    -   Pd(dppf)₂Cl₂        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   PdCl₂(dtbpf)        [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)    -   PE petroleum ether    -   PG protecting group    -   PMBNH₂ p-methoxybenzylamine    -   PMP P-methoxyphenyl    -   POCl₃ phosphorus oxychloride    -   PS polystyrene    -   RPMI Roswell Park Memorial Institute    -   RT or rt room temperature    -   sat. saturated    -   T₃P propylphosphonic anhydride solution    -   t-BuOH tert-butanol    -   TEA triethyl amine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography    -   uL microliter(s)    -   XPhos Pd G2        chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

General Synthetic Schemes

The compounds of formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and synthetic procedures and conditions for the illustrativeintermediates and examples.

In scheme 1, commercially available amine Gen-2, where R⁵=Me, Et (forexample, ethyl 1-(4-aminophenyl)cyclobutane-1-carboxylate), iselaborated to Gen-3 by treatment with Gen-1 and a base (for example,TEA). Treatment of Gen-3 with Gen-4 and a base (for example, potassiumtert-butoxide) affords Gen-5. Conversely, Gen-3 can be treated with abase (for example, NaOH) to afford Gen-6. Gen-6 can undergo amidecoupling (for example, with HATU/DIEA) with Gen-4 to afford Gen-5.

In scheme 2, commercially available carboxylic acid Gen-13 (for example,1-(4-((tert-butoxycarbonyl)amino)phenyl)cyclobutane-1-carboxylic acid)is elaborated to Gen-7 through amide coupling (for example, withHATU/DIEA) with Gen-4. Boc deprotection (for example, with 4.0 M HCl) ofGen-7 affords Gen-8. Gen-8 and Gen-9 undergo amide coupling (forexample, with HATU/DIEA) to afford Gen-5.

In scheme 3, commercially available Gen-15, where X═Br, Cl and R⁵=Me, Et(for example, methyl1-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate), is cross coupled(for example, with JackiePhos Pd G3) with commercially available Gen-16(for example, 3-chlorobenzamide) to afford Gen-17. Fluorination ofGen-17 (for example, with DAST) affords Gen-18. Treatment of Gen-18 witha base (for example, NaOH) affords Gen-19. Amide coupling (for example,HATU/DIEA) of Gen-19 with Gen-4 affords Gen-20.

In scheme 4, commercially available carboxylic acid Gen-21, where X═Br,Cl and R⁶═H, Me (for example,(1s,3s)-1-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid), iselaborated to Gen-22 through amide coupling (for example, withHATU/DIEA) with Gen-4. Cross coupling (for example, with JackiePhos PdG3) of Gen-22 with Gen-16 affords Gen-82.

In scheme 5, commercially available Gen-81, where X═Br, Cl and R⁵=Me, Et(for example, methyl 1-(4-chlorophenyl)cyclobutane-1-carboxylate), isfluorinated (for example, with DAST) to afford Gen-25. Amine formationaffords Gen-26. Treatment of Gen-26 with a base (for example, with TEA)and Gen-1 affords Gen-27. Treatment of Gen-27 with a base (for example,with NaOH) affords Gen-28. Amide coupling (for example, with HATU/DIEA)of Gen-28 with Gen-4 affords Gen-29.

In scheme 6, commercially available Gen-30, where R⁵=Me, Et (forexample, methyl 2-(4-nitrophenyl)acetate), is elaborated to Gen-31through cyclobutane installation. Gen-31 is converted to thecorresponding amine (for example, with SnCl₂) Gen-2. Gen-2 is elaboratedto Gen-3 through treatment with Gen-1 and a base (for example, TEA).Gen-3 is treated with a base (for example, NaOH) to afford Gen-6. Gen-6undergoes amide formation (for example, with HATU/DIEA) with Gen-4 toafford Gen-5.

In scheme 7, commercially available Gen-48 (for example,2-(4-nitrophenyl)acetonitrile) is elaborated to Gen-57 throughcyclobutane installation. Treatment of Gen-57 with a base (for example,KOH) affords Gen-34. Gen-34 is converted to acid chloride Gen-58(through treatment with oxalyl chloride, for example). Gen-58 isconverted to Gen-59 by treatment with a base (for example, TEA) andGen-4. Nitro reduction (for example, with Pd/C) of Gen-59 affordsGen-60. Gen-60 and Gen-1 are treated with a base (for example, TEA) toafford Gen-5.

In scheme 8, commercially available Gen-61 (for example,4-bromo-2-fluoro-1-nitrobenzene) undergoes nitro reduction (for example,with Iron) to afford Gen-62. Gen-62 is converted to Gen-63 throughtreatment with a base (for example, TEA) and Gen-1. Gen-63 is coupled(for example, with Pd₂(dba)₃/DPPF/LiHMDS) with cyclobutanecarbonitrileto afford Gen-64. Gen-64 is treated with an acid (for example, H₂SO₄) toafford Gen-65. Gen-65 is treated with a base (for example, NaOH) toafford Gen-66. Gen-66 undergoes amide coupling (for example, withHATU/DIEA) with Gen-4 to afford Gen-67.

In scheme 9, commercially available Gen-68, where R⁵=Me, Et (forexample, ethyl 2-(4-nitrophenyl)acetate), is elaborated to Gen-69through cyclobutane installation. Nitro reduction (for example, withIron) of Gen-69 affords Gen-70. Gen-70 is brominated (for example, withNBS) to afford Gen-71. Gen-9 is converted to Gen-1 (through treatmentwith, for example, oxalyl chloride). Gen-1 and Gen-71 are treated with abase (for example, TEA) to afford Gen-72. Gen-72 is treated with a base(for example, LiOH) to afford Gen-73. Gen-73 and Gen-4 undergo amidecoupling (for example, with HATU/DIEA) to afford Gen-74. Gen-74 iselaborated to Gen-75 under coupling conditions (for example, withPd(OAc)₂ and JohnPhos). Gen-75 is treated with an acid (for example,HCl) to afford Gen-76. Reduction of Gen-76 (with, for example NaBH₄)affords Gen-77.

In scheme 10, Gen-34 and Gen-4 undergo amide formation (for example,with 1. Oxalyl chloride; 2. TEA) to afford Gen-83. Nitro reduction (forexample, with Pd/C) of Gen-83 affords Gen-60. Gen-60 and Gen-9 undergoamide formation (for example, with 1. Oxalyl chloride; 2. TEA) to affordGen-5.

In scheme 11, commercially available Gen-43, where X═Br, Cl (forexample, 2-(4-bromophenyl)acetonitrile), is treated with a base (forexample, NaH) and 1,3-dibromo-2,2-dimethoxypropane to afford Gen-49.Gen-49 is treated with a base (for example, NaOH) to afford Gen-50.Gen-50 is treated with an acid (for example, H₂SO₄) to afford Gen-51.Gen-51 is fluorinated (for example, with DAST) to afford Gen-52. Gen-52is converted to a protected amine (for example, PMP protected amine) toafford Gen-53. Gen-53 is treated with a base (for example, LiOH) toafford Gen-54. Gen-54 undergoes amide coupling (for example, withHATU/DIEA) with Gen-4 to afford Gen-55. Gen-55 is deprotected (with, forexample Pd/C) to afford Gen-56. Gen-56 undergoes amide formation (forexample, with POCl₃) with Gen-9 to afford Gen-29.

In scheme 12, commercially available carboxylic acid Gen-10, whereR⁵=Me, Et (for example,1-(4-(methoxycarbonyl)phenyl)cyclobutane-1-carboxylic acid), iselaborated to Gen-11 through amide coupling (for example, withHATU/DIEA) with Gen-4. Treatment of Gen-11 with a base (such as LiOH)affords Gen-12. Gen-12 is elaborated to Gen-14 through amide coupling(for example, with HATU/DIEA) with Gen-33.

In scheme 13, commercially available Gen-30, where R⁵=Me, Et (forexample, ethyl 2-(4-nitrophenyl)acetate), is converted to Gen-31 throughthe installation of cyclobutane (for example, with NaH and1,3-diiodopropane). Treatment of Gen-31 with a base (for example, LiOH)affords Gen-34. Gen-34 is converted (for example, via DPPA/TEA) to a bocprotected amine Gen-35. Nitro reduction of Gen-35 (for example, withIron) affords Gen-36. Gen-36 is converted to amide Gen-37 (for example,via T₃P/pyridine) with addition of Gen-9. Gen-37 is converted to Gen-38through boc deprotection (for example, with HCl). Gen-38 is elaboratedto Gen-39 through amide coupling (for example, HATU/DIEA) with Gen-9.

In scheme 14, commercially available Gen-40 where X═Br, Cl (for example,1-(4-bromophenyl)cyclobutan-1-amine) is elaborated to Gen-41 throughamide coupling (for example, with HATU/DIEA) with Gen-32. Gen-41 iselaborated to Gen-42 through coupling (for example, with Cu(I)I) withGen-1.

In scheme 15, commercially available Gen-30, where R⁵=Me, Et (forexample, ethyl 2-(4-nitrophenyl)acetate), is converted to Gen-31 throughthe installation of cyclobutane (for example, with NaH and1,3-diiodopropane). Treatment of Gen-31 with a base (for example, LiOH)affords Gen-34. Gen-34 is converted (for example, via DPPA/TEA) to a bocprotected amine Gen-35. Gen-35 undergoes boc deprotection (for example,with HCl) to afford Gen-44. Gen-44 is elaborated to Gen-45 through amidecoupling (for example, with HATU/DIEA) with Gen-32. Gen-45 is convertedto the corresponding amine (for example, with treatment withIron/NH₄Cl), Gen-46. Gen-46 is treated with a base (for example, TEA)and Gen-1 to afford Gen-39.

In scheme 16, Gen-22 (see scheme 4) is methylated to afford Gen-80.Gen-80 undergoes cross coupling (for example, with JackiePhos Pd G3)with Gen-16 to afford Gen-84.

Standard purification procedures referenced in the following examplesare provided below.

Purification A: TFA (Acidic) Conditions/Chromatography and MassSpectrometry

Isolation of a compound from the reaction mixture was carried out underreverse-phase purification using an Agilent 1200 HPLC-MSD systemconsisting of a 6130B single quadrupole mass-selective detector (MSD),G1315B diode array detector (DAD), G2258A autosampler, two G1361Apreparative pumps, one G1379A quaternary pump with degasser, one G1312Abinary pump, and three G1364B fraction collectors from AgilentTechnologies (Agilent Technologies, Palo Alto, Calif.). System controland data analysis were performed using Agilent's ChemStation software,revision B.04.03. A Waters SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×150 mm column was used as the stationary phase (Waters Corporation,Milford, Mass., USA). Gradient elution was carried out using water(solvent A) and acetonitrile (solvent B) as a mobile phase. A 10%trifluoroacetic acid solution was added into the mobile phase as amodifier using a static mixer prior to the column, pumped at 1% of thetotal mobile phase flowrate. Electrospray (ESI) Mass-triggered fractioncollected was employed using positive ion polarity scanning to monitorfor the target mass.

HPLC Gradient:

Time Mobile Phase Flowrate Modifier Flowrate (min) % Acetonitrile(mL/Min) (mL/min) 0.0 2 25 0.25 3.0 2 35 0.35 33.0 95 35 0.35 33.1 10040 0.4 36.1 100 50 0.5 36.8/end 2 25 0.2Purification B: TFA (Acidic) Condition/Chromatography and MassSpectrometry

Isolation of a compound from the reaction mixture was carried out underreverse-phase purification using a Gilson system consisting of UV-156detector, GX281 liquid handler, 322 pumps. An Agela ASB 150*25 mm*5 mcolumn was used as the stationary phase. Gradient elution was carriedout using water (solvent A) and acetonitrile (solvent B) as a mobilephase. A 0.1% trifluoroacetic acid solution was added into the mobilephase (solvent A) as a modifier.

HPLC Gradient:

Time Mobile Phase Flowrate (min) % Acetonitrile (mL/Min) 0.0 37 25 1.037 25 10.0 52 25 10.2 100 25 12.5 100 25 12.7/end 5 25Purification C: TFA (Acidic) Condition/Chromatography and MassSpectrometry

Isolation of a compound from the reaction mixture was carried out underreverse-phase purification using a Gilson system consisting of UV-156detector, GX281 liquid handler, 322 pumps. An Agela ASB 150*25 mm*5 mcolumn was used as the stationary phase. Gradient elution was carriedout using water (solvent A) and acetonitrile (solvent B) as a mobilephase. A 0.2% trifluoroacetic acid solution was teed into the mobilephase (solvent A) as a modifier.

HPLC Gradient:

Time Mobile Phase Flowrate (min) % Acetonitrile (mL/Min) 0.0 37 25 1.037 25 10.0 52 25 10.2 100 25 12.5 100 25 12.7/end 5 25Purification D: Formic Acid (Acidic) Condition/Chromatography and MassSpectrometry

Isolation of a compound from the reaction mixture was carried out underreverse-phase purification using a Gilson system consisting of UV-156detector, GX281 liquid handler, 322 pumps. An Agela ASB 150*25 mm*5 μmcolumn was used as the stationary phase. Gradient elution was carriedout using water (solvent A) and acetonitrile (solvent B) as a mobilephase. A 0.2% formic acid solution was teed into the mobile phase(solvent A) as a modifier.

HPLC Gradient:

Time Mobile Phase Flowrate (min) % Acetonitrile (mL/Min) 0.0 37 25 1.037 25 10.0 52 25 10.2 100 25 12.5 100 25 12.7/end 5 25

EXAMPLES Example 1:N-(4-(1-Butyramidocyclobutyl)phenyl)-3-chlorobenzamide

Step 1: Preparation of N-(1-(4-bromophenyl)cyclobutyl)butyramide

To a vial containing butyric acid (52 μl, 0.57 mmol) and HATU (280 mg,0.74 mmol) was added DMF (2100 μl). The reaction mixture was allowed tostir at RT for 5 min, before a solution of1-(4-bromophenyl)cyclobutanamine (150 mg, 0.64 mmol) in DMF (710 μl) wasadded, followed by DIPEA (350 μl, 2.0 mmol). The reaction mixture wasstirred at RT for 5 days, then partitioned between EtOAc and saturatedNaHCO₃. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to affordN-(1-(4-bromophenyl)cyclobutyl)butyramide. MS ESI calc'd. [M+H]⁺ 296,found 296.

Step 2: Preparation ofN-(4-(1-butyramidocyclobutyl)phenyl)-3-chlorobenzamide

To a vial equipped with a stir bar was addedN-(1-(4-bromophenyl)cyclobutyl)butyramide (30 mg, 0.10 mmol), cesiumcarbonate (99 mg, 0.30 mmol), 3-chlorobenzamide (15 mg, 0.099 mmol),(1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (2.9 mg, 0.020 mmol), anddioxane (510 μl). The reaction mixture was purged with nitrogen, beforecopper(I) iodide (1.9 mg, 10 μmol) was added. The reaction mixture waspurged with nitrogen for 3 min. The vial was sealed and heated to 110°C. for 25 h. The crude reaction mixture was cooled to RT, dissolved inmethanol and filtered over Celite. The filtrate was concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica (0-100% EtOAc/hexanes) to affordN-(4-(1-butyramidocyclobutyl)phenyl)-3-chlorobenzamide. The material wasthen dissolved in DMSO (1 ml), filtered, and purified under PurificationA conditions to afford the title compound. MS ESI calc'd. [M+H]⁺ 370,found 393 (M+Na⁺). ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.44 (s,1H), 8.04 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.61(t, J=7.9 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 2.46 (t, J=7.5 Hz, 3H), 2.09(t, J=7.2 Hz, 2H), 2.05-1.96 (m, 1H), 1.90-1.77 (m, 1H), 1.56-1.47 (m,2H), 0.87 (t, J=7.4 Hz, 3H).

Example 2:3-Chloro-N-(4-(1-(4-cyanobenzamido)cyclobutyl)phenyl)benzamide

Step 1: Preparation of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate

To a solution of ethyl 2-(4-nitrophenyl)acetate (9 g, 43 mmol) in DMF(100 mL) was added NaH (3.6 g, 90 mmol) (60% in oil) at 0° C. Thereaction mixture was allowed to warm to RT and was stirred for 15 min.The mixture was cooled to 0° C. and 1,3-diiodopropane (10 mL, 89 mmol)was added. The resulting mixture was stirred at 0° C. for 30 min, thenwarmed to RT. After 1 h the reaction mixture was diluted with aqueousNH₄Cl (200 mL), and was extracted with EtOAc (200 mL×3). The combinedorganics were washed with brine (1000 mL), dried over saturated Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (SiO₂, petroleum ether/EtOAc=50:1to 40:1) to afford ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate.

Step 2: Preparation of 1-(4-nitrophenyl)cyclobutanecarboxylic Acid

To a solution of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate (6.6 g,26 mmol) in THF (80 mL)/MeOH (80 mL)/water (40 mL) was added lithiumhydroxide hydrate (3.3 g, 79 mmol) at RT. The reaction was stirred at RTfor 15 h then concentrated under reduced pressure. The residue wasacidified to pH ˜5 with 3 M HCl then extracted with EtOAc (100 mL×3).The combined organics were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica column chromatography (petroleumether:EtOAc=4:1) to afford 1-(4-nitrophenyl)cyclobutanecarboxylic acid.

Step 3: Preparation of tert-butyl (1-(4-nitrophenyl)cyclobutyl)carbamate(Intermediate 1)

To a solution of 1-(4-nitrophenyl)cyclobutanecarboxylic acid (3.9 g, 18mmol) in t-BuOH (80 mL) was added TEA (3.7 mL, 27 mmol) and diphenylphosphorazidate (5.6 g, 21 mmol) while stirring at RT. The reactionmixture was heated and stirred at 85° C. under N₂ for 2 h, cooled to RT,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (petroleum ether: ethyl acetate=20:1)to afford tert-butyl (1-(4-nitrophenyl)cyclobutyl)carbamate.

Step 4: Preparation of tert-butyl (1-(4-aminophenyl)cyclobutyl)carbamate

To a stirred solution of tert-butyl(1-(4-nitrophenyl)cyclobutyl)carbamate (3.7 g, 13 mmol) (Intermediate 1)in ethanol (50 mL) and water (5 mL) was added iron (3.5 g, 63 mmol) andNH₄Cl (6.8 g, 130 mmol). The reaction mixture was stirred at 90° C. for3 h, cooled to RT, and filtered through a pad of Celite. The filtratewas concentrated under reduced pressure. The residue was dissolved inDCM (150 mL), and washed with water (100 mL) and brine (50 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicacolumn chromatography (petroleum ether:EtOAc=5:1) to afford tert-butyl(1-(4-aminophenyl)cyclo-butyl)carbamate.

Step 5: Preparation of tert-butyl(1-(4-(3-chlorobenzamido)phenyl)cyclobutyl)carbamate

To a stirred solution of 3-chlorobenzoic acid (2.1 g, 14 mmol) in THF(100 mL) was added tert-butyl (1-(4-aminophenyl)cyclobutyl)carbamate(3.0 g, 11 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (15 g, 22.87 mmol) (50% in the EtOAc), and pyridine (2.77mL, 34 mmol). The reaction mixture was stirred at RT for 3 h, thenconcentrated under reduced pressure. The residue was dissolved in DCM(100 mL), washed with water (100 mL), and the organic layer wasconcentrated under reduced pressure to afford tert-butyl(1-(4-(3-chlorobenzamido)phenyl)cyclobutyl)carbamate.

Step 6: Preparation of N-(4-(1-aminocyclobutyl)phenyl)-3-chlorobenzamide(Intermediate 2)

To a solution of tert-butyl(1-(4-(3-chlorobenzamido)phenyl)cyclobutyl)carbamate (1.6 g, 3.99 mmol)in 1,4-dioxane (20 mL) was added hydrogen chloride (30 mL, 120 mmol) (4Min dioxane) drop wise while stirring at RT. The reaction mixture wasallowed to stir at RT for 15 h, then concentrated under reducedpressure. The residue was purified under Purification B conditions toafford N-(4-(1-aminocyclobutyl)phenyl)-3-chlorobenzamide.

Step 7: Preparation of3-Chloro-N-(4-(1-(4-cyanobenzamido)cyclobutyl)phenyl)benzamide

To a vial equipped with a stir bar was added 4-cyanobenzoic acid (14 mg,0.083 mmol) in DMF (1.0 ml) and HATU (38 mg, 0.10 mmol). The reactionmixture was stirred for 5 min beforeN-(4-(1-aminocyclobutyl)phenyl)-3-chlorobenzamide (25 mg, 0.083 mmol)(Intermediate 2) was added, followed by DIEA (0.044 ml, 0.25 mmol). Thereaction mixture was stirred for 12 h at RT, and was then filtered andpurified under Purification A conditions to afford the title compound.MS ESI calc'd. [M+H]⁺ 430, found 430. ¹H NMR (500 MHz, DMSO-d₆) δ 10.31(s, 1H), 8.51 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.66(s, 3H), 7.56 (s, 1H), 7.43 (s, 2H), 6.53 (s, 1H), 3.37 (s, 2H), 2.62(s, 2H), 1.97 (s, 1H), 1.79 (s, 1H).

Examples 3-17 in Table 1 were prepared in an analogous way to Example 2,using the corresponding carboxylic acid. Example 18 can be prepared inan analogous way to Example 2, using T₃P and pyridine in the final stepwith the corresponding carboxylic acids.

TABLE 1 Ex. # Structure Chemical Name Mass [M + H]+ 3

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)pyrazine-2- carboxamide 407 4

3-chloro-N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)pyridine-2- carboxamide 440 5

4-chloro-N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)pyridine-2- carboxamide 440 6

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-1-methyl-1H- imidazole-2-carboxamide 409 7

6-chloro-N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)pyridine-3- carboxamide 440 8

4-chloro-N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-3- fluorobenzamide 457 9

5-chloro-N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)pyridine-2- carboxamide 440 10

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl} cyclobutyl)-3,4-difluorobenzamide 441 11

3,4-dichloro-N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)benzamide 473 12

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-1,3-oxazole-2- carboxamide 396 13

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-1-methyl-1H- pyrazole-3-carboxamide 409 14

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-1,3-thiazole-4- carboxamide 412 15

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-1,3-thiazole-2- carboxamide 412 16

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)-1,3-oxazole-4- carboxamide 396 17

N-(4-{1-[(4- chlorobenzene-1- carbonyl)amino]cyclobutyl}phenyl)pyrimidine-5- carboxamide 407 18

N-(1-{4-[(3- chlorobenzene-1- carbonyl)amino]phenyl}cyclobutyl)pyrimidine-5- carboxamide 407

Example 19:3-Chloro-N-(4-(1-(4-chlorobenzamido)cyclobutyl)phenyl)benzamide

Step 1: Preparation of 1-(4-Nitrophenyl)cyclobutan-1-amine

A mixture of tert-butyl (1-(4-nitrophenyl)cyclobutyl)carbamate(Intermediate 1) (250 mg, 0.86 mmol) and HCl (4 mL, 16 mmol) (4M indioxane) was stirred at RT for 2 h, then concentrated under reducedpressure to afford 1-(4-nitrophenyl)cyclobutanamine hydrochloride.

Step 2: Preparation of 4-chloro-N-(1-(4-nitrophenyl)cyclobutyl)benzamide

To a solution of 1-(4-nitrophenyl)cyclobutanamine hydrochloride (200 mg,0.86 mmol) in DMF (5 mL) was added HATU (330 mg, 0.87 mmol),4-chlorobenzoic acid (140 mg, 0.87 mmol) and DIEA (0.6 mL, 3.4 mmol)while stirring at RT. The reaction mixture was allowed to stir for 15 h,and was then diluted with water (30 mL), and extracted with EtOAc (20mL×3). The combined organics were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica column chromatography (petroleumether:EtOAc=20:1 to 1:1) to afford4-chloro-N-(1-(4-nitrophenyl)cyclobutyl)benzamide.

Step 3: Preparation of N-(1-(4-aminophenyl)cyclobutyl)-4-chlorobenzamide(Intermediate 3)

To a stirred solution of4-chloro-N-(1-(4-nitrophenyl)cyclobutyl)benzamide (150 mg, 0.45 mmol) inEtOH (5 mL)/water (0.5 mL) was added iron (130 mg, 2.3 mmol) and NH₄Cl(240 mg, 4.5 mmol). The reaction was stirred at 90° C. for 2 h, cooledto RT, then filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure to affordN-(1-(4-aminophenyl)cyclobutyl)-4-chlorobenzamide. MS ESI calc'd. [M+H]⁺301, found 301.

Step 4: Preparation of3-chloro-N-(4-(1-(4-chlorobenzamido)cyclobutyl)phenyl)benzamide

To a solution of N-(1-(4-aminophenyl)cyclobutyl)-4-chlorobenzamide (130mg, 0.43 mmol) (Intermediate 3) and TEA (0.2 mL, 1.4 mmol) in DCM (5 mL)was added 3-chlorobenzoyl chloride (150 mg, 0.86 mmol) in DCM (5 mL) at0° C. The reaction was stirred at 0° C. for 1 h, then concentrated underreduced pressure. The residue was partitioned between water (20 mL) andEtOAc (10 mL×2). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified under Purification B conditions to afford the title compound.MS ESI calc'd. [M+H]⁺ 439, found 461 (M+Na⁺). ¹H NMR (400 MHz, DMSO-d₆)δ 10.30 (s, 1H), 9.06 (s, 1H), 7.98 (t, J=1.6 Hz, 1H), 7.84-7.91 (m,3H), 7.62-7.70 (m, 3H), 7.48-7.58 (m, 3H), 7.44 (d, J=8.6 Hz, 2H),2.51-2.65 (m, 4H), 1.94-2.04 (m, 1H), 1.76-1.89 (m, 1H).

Example 20:3-Chloro-N-(4-(1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of ethyl1-(4-(3-chlorobenzamido)phenyl)cyclobutane-1-carboxylate (Intermediate4)

Ethyl 1-(4-aminophenyl)cyclobutanecarboxylate (1050 mg, 4.8 mmol) wasdissolved in DCM (20 ml) and cooled to 0° C. using an ice bath. Et₃N(1.0 ml, 7.2 mmol) and 3-chlorobenzoyl chloride (0.77 ml, 6.1 mmol) wereadded to the solution drop wise at 0° C. The mixture was stirred at RTfor 18 h. After 18 h the crude reaction mixture was concentrated underreduced pressure and purified on silica gel (100 g flash column, EtOAcin hexane, 0-20%, 5 CV; 20-20%, 10 CV) to afford ethyl1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate. MS (ESI) Calc'd[M+H]⁺, 358; found, 358.

Step 2: Preparation of3-chloro-N-(4-(1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide(Compound 20)

To a solution of KOtBu (27 mg, 0.24 mmol) in THF (600 μl) was addedethyl 1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate (31 mg,0.087 mmol) (Intermediate 4) and 4-fluoroaniline (10 μl, 0.11 mmol). Themixture was stirred at RT for 20 h. After 20 h the mixture was dilutedwith MeOH, filtered and purified under Purification A conditions toafford the title compound. MS (ESI) Calc'd [M+H]⁺, 423; found, 423. ¹HNMR (600 MHz, DMSO-d₆) δ 10.31 (s, 1H), 9.41 (s, 1H), 7.95 (s, 1H), 7.86(d, J=7.7 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.57(dd, J=8.3, 5.1 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H),7.06 (t, J=8.7 Hz, 2H), 2.77 (q, J=8.5 Hz, 2H), 2.41 (q, J=8.7 Hz, 2H),1.85-1.70 (m, 2H).

Examples 21-23: 1-(4-(3-Chlorobenzamido)phenyl)cyclobutane-1-carboxylicAcid

Step 1: Preparation of1-(4-(3-chlorobenzamido)phenyl)cyclobutane-1-carboxylic Acid

To a solution of ethyl1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate (1.7 g, 4.7 mmol)(Intermediate 4) in THF (10 ml), was added 1 M NaOH (10 ml, 10 mmol) andethanol (10 ml). The mixture was stirred at RT for 18 h. An additional 5ml of NaOH (1M) was added and the reaction was stirred at RT for anadditional 18 h. After 18 h the crude reaction mixture was partiallyconcentrated under reduced pressure. To the remaining aqueous solutionwas added HCl (1 M), to adjust the pH to ˜3. The solution was extractedwith EtOAc (3 times). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure to afford 1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylicacid. MS (ESI) Calc'd [M+H]⁺, 330; found, 330.

Step 2: Preparation of3-chloro-N-(4-(1-((2-methylcyclopropyl)carbamoyl)cyclobutyl)phenyl)benzamide

To a vial was added 1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylicacid (201.7 mg, 0.612 mmol), HATU (285.7 mg, 0.751 mmol), DMF (3500 μl),2-methylcyclopropanamine (81.9 mg, 1.15 mmol) and DIEA (200 μl, 1.15mmol). The mixture was stirred at RT for 18 h, then concentrated underreduced pressure. The residue was purified by silica gel chromatography(25 g flash column, EtOAc in hexane, 0-50%, 6 CV; 50%-50%, 6 CV) toafford3-chloro-N-(4-(1-((2-methylcyclopropyl)carbamoyl)cyclobutyl)phenyl)benzamide.MS (ESI) Calc'd [M+H]⁺, 383 found, 383.

Step 3: Chiral Resolution of3-chloro-N-(4-(1-((2-methylcyclopropyl)carbamoyl)cyclobutyl)phenyl)benzamide(Examples 21, 22 and 23)

Preparative resolution of3-chloro-N-(4-(1-((2-methylcyclopropyl)carbamoyl)cyclobutyl)phenyl)benzamidewas performed using supercritical fluid chromatography on a SepiatecPrep SFC 100. A Chiralpak IC column (5 m, 21 mm×250 mm, ChiralTechnologies Inc., West Chester, Pa.) was used as the chiral stationaryphase. The compound mixture was dissolved in methanol. Injection andcollection were carried out using the following isocratic SFCconditions: 80% carbon dioxide and 20% methanol with 0.25% dimethylethylamine as the mobile phase, 220 nm UV wavelength, 100 bar outletpressure, 40° C. column compartment temperature, 70 mL/min total flowrate. Retention times for peak collection were as follows: Example 21(isomer 1), 6.0 min; Example 22 (isomer 2), 7.2 min; and Example 23(isomer 3), 8.9 min.

Peak 3 (Ex. 23): MS (ESI) Calc'd [M+H]⁺, 383; found, 383. ¹H NMR (600MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=7.7 Hz, 1H),7.75-7.78 (m, 3H), 7.61 (t, J=7.8 Hz, 1H), 7.41 (d, J=3.2 Hz, 1H), 7.36(d, J=8.4 Hz, 2H), 2.78-2.65 (m, 2H), 2.42-2.32 (m, 2H), 1.87-1.73 (m,2H), 0.78-0.69 (m, 4H), 0.28-0.21 (m, 1H).

Examples 24-44 in Table 2 were prepared in an analogous way to Examples21, 22 and 23 using the corresponding amines in Step 2.

TABLE 2 Ex. # Structure Chemical Name Mass [M + H]+ 24

3-chloro-N-(4-{1-[(4- chlorophenyl)carbamoyl] cyclobutyl}phenyl)benzamide 439 25

3-chloro-N-(4-{1-[(2,4- difluorophenyl)carbamoyl] cyclobutyl}phenyl)benzamide 441 26

3-chloro-N-(4-{1-[(3,4- difluorophenyl)carbamoyl] cyclobutyl}phenyl)benzamide 441 27

3-chloro-N-(4-{1-[(6- chloropyridin-3- yl)carbamoyl]cyclobutyl}phenyl)benzamide 440 28

3-chloro-N-(4-{1-[(5- fluoropyridin-2- yl)carbamoyl]cyclobutyl}phenyl)benzamide 424 29

3-chloro-N-(4-{1-[(6- fluoropyridin-3- yl)carbamoyl]cyclobutyl}phenyl)benzamide 424 30

3-chloro-N-{4-[1- (cyclohexylcarbamoyl) cyclobutyl]phenyl} benzamide 41131

3-chloro-N-(4-{1-[(2- ethylcyclopropyl) carbamoyl]cyclobutyl}phenyl)benzamide 397 32

3-chloro-N-[4-(1- {[(1R;2R)-2- (trifluoromethyl) cyclopropyl]carbamoyl}cyclobutyl) phenyl[benzamide 437 33

3-chloro-N-(4-{1-[(4,4- difluorocyclohexyl) carbamoyl]cyclobutyl}phenyl) benzamide 447 34

3-chloro-N-(4-{1-[(oxan- 4- yl)carbamoyl]cyclobutyl} phenyl) benzamide413 35

3-chloro-N-(4-{1-[(1- methyl-1H-pyrazol-3- yl)carbamoyl]cyclobutyl}phenyl)benzamide 409 36

3-chloro-N-(4-{1-[(2- ethoxycyclopropyl) carbamoyl]cyclobutyl} phenyl)benzamide 413 37

3-chloro-N-[4-(1-{[2- (difluoromethyl) cyclopropyl]carbamoyl}cyclobutyl)phenyl] benzamide 419 38

3-chloro-N-(4-{1-[(3,3- difluorocyclobutyl) carbamoyl]cyclobutyl}phenyl) benzamide 419 39

N-(4-{1- [(bicyclo[1.1.1]pentan-1- yl)carbamoyl]cyclobutyl} phenyl)-3-chlorobenzamide 395 40

3-chloro-N-(4-{1-[(oxan- 3- yl)carbamoyl]cyclobutyl} phenyl)benzamide413 41

3-chloro-N-(4-{1-[(1- cyclopropylethyl) carbamoyl]cyclobutyl}phenyl)benzamide 397 42

3-chloro-N-(4-{1-[(2,2- dimethyloxan-4- yl)carbamoyl]cyclobutyl}phenyl)benzamide 441 43

3-chloro-N-[4-(1-{[1- (oxolan-2- yl)ethyl]carbamoyl}cyclobutyl)phenyl]benzamide 427 44

3-chloro-N-[4-(1-{[1- (2,2,2- trifluoroethyl)azetidin-3-yl]carbamoyl}cyclobutyl) phenyl]benzamide 466

Example 45:3-Chloro-N-(4-(1-((2-ethoxypropyl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of methyl 1-(4-nitrophenyl)cyclobutane-1-carboxylate

A solution of methyl 2-(4-nitrophenyl)acetate (6 g, 31 mmol) in DMF (100ml) was cooled to 0° C. with an ice bath. NaH (60% in oil) (2.5 g, 63mmol) was added portion wise. The resulting mixture was allowed to warmto RT and was stirred for 15 min at RT. After 15 min the mixture wascooled again to 0° C. and 1,3-diiodopropane (6 ml, 52 mmol) was addeddrop wise. The resulting mixture was allowed to stir at 0° C. for 30min, and from 0° C. to 10° C. for 1.5 h. After 1.5 h the solution wascooled to 0° C. and water was added. The reaction mixture was extracted3 times with DCM. The combined organics were concentrated under reducedpressure and the residue was purified by flash chromatography on silica(120 g flash column, 0-20% EtOAc in hexane, 10 CV) to afford methyl1-(4-nitrophenyl)cyclobutanecarboxylate.

Step 2: Preparation of methyl 1-(4-aminophenyl)cyclobutane-1-carboxylate

To a flask was added methyl 1-(4-nitrophenyl)cyclobutanecarboxylate (970mg, 4.1 mmol), Ethanol (10 ml) and tin(II)chloride (3100 mg, 16 mmol).The reaction mixture was heated to 85° C. and was stirred for 4 h. After4 h the reaction mixture was cooled to RT, and the pH was adjusted to˜10 by adding concentrated aq. NaOH dropwise. The mixture was extractedwith EtOAc (4 times). The combined organic layers were washed withwater, brine, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to afford methyl1-(4-aminophenyl)cyclobutanecarboxylate. MS (ESI) Calc'd [M+H]⁺, 206;found, 206.

Step 3: Preparation of methyl1-(4-(3-chlorobenzamido)phenyl)cyclobutane-1-carboxylate

Methyl 1-(4-aminophenyl)cyclobutanecarboxylate (850 mg, 4.1 mmol) wasdissolved in DCM (10 ml) and cooled to 0° C. using an ice bath. Et₃N(700 μl, 5.0 mmol) was added, then 3-chlorobenzoyl chloride (600 μl, 4.7mmol) was added to the solution drop wise at 0° C. The mixture wasstirred while warming to RT over 18 h. After 18 h the reaction mixturewas concentrated under reduced pressure and purified by flashchromatography on silica (Silicycle, 40 g, EtOAc in hexane, 0-20%, 5 CV;20-20%, 10 CV) to afford methyl1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate. MS (ESI) Calc'd[M+H]+, 344; found, 344.

Step 4: Preparation of1-(4-(3-chlorobenzamido)phenyl)cyclobutane-1-carboxylic Acid

To the solution of methyl1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate (1.0 g, 3.0 mmol)in THF (12 ml) was added NaOH (10 ml, 10 mmol, 1M). MeOH (5 ml) wasadded and the mixture was stirred at RT for 18 h. After 18 h thereaction mixture was concentrated under reduced pressure. To theresulting aqueous solution was added HCl (1 M) to adjust the pH to ˜3.The solution was washed with EtOAc 3 times. The combined organics werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to afford1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylic acid. MS (ESI)Calc'd [M+H]⁺, 330; found, 330.

Step 5: Preparation of3-chloro-N-(4-(1-((2-ethoxypropyl)carbamoyl)cyclobutyl)phenyl)benzamide(Compound 45)

To a vial was added 1-(4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylicacid (15 mg, 0.045 mmol), HATU (30 mg, 0.079 mmol),2-ethoxypropan-1-amine (15 mg, 0.145 mmol), DMF (300 μl) and DIEA (30μl, 0.172 mmol). The mixture was stirred at RT for 4 h. After 4 h themixture was filtered and purified under Purification A conditions toafford the title compound. MS (ESI) Calc'd [M+H]⁺, 415; found, 415. ¹HNMR (600 MHz, DMSO-d₆) δ 10.27 (s, 1H), 7.96 (s, 1H), 7.87 (d, J=7.7 Hz,1H), 7.66 (d, J=8.1 Hz, 2H), 7.64-7.60 (m, 1H), 7.53 (t, J=7.8 Hz, 1H),7.38 (t, J=5.6 Hz, 1H), 7.27 (d, J=8.3 Hz, 2H), 3.37-3.25 (m, 2H), 3.21(p, J=7.0 Hz, 1H), 3.01-2.90 (m, 2H), 2.85-2.48 (m, 2H), 2.37-2.23 (m,2H), 1.83-1.64 (m, 2H), 0.95 (t, J=6.9 Hz, 3H), 0.86 (d, J=6.1 Hz, 3H).

Examples 46-53 and 88 in Table 3 were prepared using an analogous way toExample 45, using the corresponding amines in Step 5.

TABLE 3 Ex. # Structure Chemical Name Mass [M + H]+ 46

3-chloro-N-(4-{1-[(2- methylcyclopropyl) carbamoyl]cyclobutyl} phenyl)benzamide 383 47

3-chloro-N-(4-{1- [(3,3,3- trifluoropropyl) carbamoyl]cyclobutyl}phenyl)benzamide 425 48

3-chloro-N-(4-{1- [(cyclopropylmethyl) carbamoyl]cyclobutyl}phenyl)benzamide 383 49

3-chloro-N-(4-{1- [(2,2,2- trifluoroethyl)carbamoyl] cyclobutyl}phenyl)benzamide 411 50

3-chloro-N-{4-[1- (ethylcarbamoyl)cyclobutyl phenyl}benzamide 357 51

3-chloro-N-[4-(1- {[(3S)-oxolan-3- yl]carbamoyl}cyclobutyl)phenyl]benzamide 399 52

3-chloro-N-[4-(1- {[(3R)-oxolan-3- yl]carbamoyl}cyclobutyl)phenyl]benzamide 399 53

3-chloro-N-(4-{1- [(phenylsulfonyl) carbamoyl]cyclobutyl}phenyl)benzamide 469 88

N-(4-{1-[(6- chloropyridin-3- yl)carbamoyl]cyclobutyl} phenyl)-3-cyanobenzamide 431

Example 54:5-Methyl-N-(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)-1,2,3-thiadiazole-4-carboxamide

Step 1: Preparation of tert-butyl(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)carbamate

To a flask was added1-(4-((tert-butoxycarbonyl)amino)phenyl)cyclobutanecarboxylic acid (1 g,3.4 mmol), HATU (1600 mg, 4.1 mmol), DCM (25 ml), DIEA (2.0 ml, 11 mmol)and propan-1-amine (380 mg, 6.4 mmol). The mixture was stirred at RT for18 h. After 18 h the mixture was washed with water, followed by brine.The combined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified on silicagel (40 g flash column, EtOAc in hexane, 0-40%, 15 CV) to affordtert-butyl (4-(1-(propylcarbamoyl)cyclobutyl)phenyl)carbamate. MS (ESI)Calc'd [M+H]⁺, 333; found, 333.

Step 2: Preparation of1-(4-aminophenyl)-N-propylcyclobutane-1-carboxamide

To the flask containing tert-butyl(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)carbamate (950 mg, 2.9 mmol)was added dioxane (10 ml) and 4 M HCl in dioxane (10 ml, 40 mmol). Themixture was stirred at RT for 16 h. After 16 h the reaction mixture wasconcentrated under reduced pressure to afford1-(4-aminophenyl)-N-propylcyclobutanecarboxamide, HCl. MS (ESI) Calc'd[M+H]⁺, 233; found, 233.

Step 3: Preparation of5-methyl-N-(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)-1,2,3-thiadiazole-4-carboxamide

To a vial was added 1-(4-aminophenyl)-N-propylcyclobutanecarboxamide,HCl (15 mg, 0.056 mmol), HATU (32 mg, 0.084 mmol),5-methyl-1,2,3-thiadiazole-4-carboxylic acid (14 mg, 0.097 mmol), DMF(300 μl) and DIEA (100 μl, 0.57 mmol). The mixture was stirred at RT for18 h. After 18 h the mixture was filtered and purified underPurification A conditions to afford the title compound. MS (ESI) Calc'd[M+H]⁺, 359; found, 359. ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.73(d, J=8.6 Hz, 2H), 7.50 (t, J=5.7 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 3.32(s, 3H), 2.95 (q, J=6.6 Hz, 2H), 2.73-2.58 (m, 2H), 2.39-2.26 (m, 2H),1.89-1.64 (m, 2H), 1.41-1.27 (m, 2H), 0.72 (t, J=7.4 Hz, 3H).

Examples 55-58 in Table 4 were prepared in an analogous way to Example54, using the corresponding carboxylic acids in Step 3.

TABLE 4 Ex. # Structure Chemical Name Mass [M + H]+ 55

4-(aminomethyl)-N-{4-[1- (propylcarbamoyl) cyclobutyl]phenyl} benzamide366 56

3-methyl-N-{4-[1- (propylcarbamoyl) cyclobutyl]phenyl}- 1,2-oxazole-5-carboxamide 342 57

2-ethyl-N-{4-[1- (propylcarbamoyl) cyclobutyl] phenyl}-1,3-oxazole-4-carboxamide 356 58

N-{4-[1- (propylcarbamoyl) cyclobutyl] phenyl}imidazo[1,2-b]pyridazine-2- carboxamide 378

Example 59:N-(3-chloro-2-fluorophenyl)-4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzamide

Step 1: Preparation of methyl4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoate

1-(4-(methoxycarbonyl)phenyl)cyclobutanecarboxylic acid (2000 mg, 8.5mmol) and oxalyl chloride (0.75 ml, 8.5 mmol) were stirred in DCM (10.0ml)/DMF (0.2 ml). The reaction mixture was stirred at RT for 4 h. After4 h the reaction mixture was concentrated under reduced pressure. To theresidue was added a mixture of 2-amino-5-fluoropyridine (960 mg, 8.5mmol) in pyridine (10 ml), and the mixture was cooled to 0° C. Themixture was slowly warmed to RT and stirred for 15 h. After 15 h thereaction mixture was concentrated under reduced pressure and purified bycolumn chromatography on silica gel (DCM/MeOH; 0-10%) to afford methyl4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoate. MS (ESI)Calc'd [M+H]⁺, 329; found, 329.

Step 2: Preparation of4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoic Acid

To a vial containing methyl4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoate (1000 mg, 3.1mmol) in THF (4.0 ml) and MeOH (1.33 ml) was added LiOH in water (6.1ml, 12 mmol). The mixture was stirred at RT for 24 h. After 24 h thecrude reaction mixture was concentrated under reduced pressure. Theresulting aqueous solution was acidified to pH ˜3 by adding HCl (1M)drop wise. The residue was washed with DCM (3 times). The combinedorganic phase was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure to afford4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoic acid. MS (ESI)Calc'd [M+H]⁺, 315; found, 315.

Step 3: PreparationN-(3-chloro-2-fluorophenyl)-4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzamide

A 20 mL vial was charged with4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoic acid (30 mg,0.095 mmol) and DMF (2.0 ml). HATU (44 mg, 0.12 mmol) was added to thereaction mixture, and the reaction mixture was allowed for stir for 5min. After 5 min 3-chloro-2-fluoroaniline (14 mg, 0.095 mmol) was added,followed by DIEA (0.10 ml, 0.57 mmol). The reaction was stirred for 24 hat 50° C. After 24 h EtOAc was added, and the reaction mixture waswashed with 3 portions of 1 N aqueous HCl, 2 portions of water, 1portion of brine, and 1 portion of saturated aqueous NaHCO₃. Thecombined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified underPurification A conditions to afford the title compound. MS (ESI) Calc'd[M+H]⁺, 442; found, 442. ¹H NMR (400 MHz, DMSO-d₆) δ 10.25 (s, 1H),10.22 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.95 (s, 2H), 7.72 (s, 1H),7.64 (s, 2H), 7.56 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 2.91 (s, 3H),1.82 (s, 3H).

Examples 60-61 in Table 5 were prepared in an analogous manner toExample 59, using the corresponding amines in Step 3.

TABLE 5 Ex. # Structure Chemical Name Mass [M + H]+ 60

N-cyclohexyl-4-{1-[(5- fluoropyridin-2- yl)carbamoyl]cyclobutyl}benzamide 396 61

N-(4,4- difluorocyclohexyl)-4-{1- [(5-fluoropyridin-2-yl)carbamoyl]cyclobutyl} benzamide 432

Example 62:3-Chloro-N-(4-(3-fluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of methyl1-(4-(3-chlorobenzamido)phenyl)-3-hydroxycyclobutane-1-carboxylate

To a vial was added methyl1-(4-bromophenyl)-3-hydroxycyclobutanecarboxylate (250 mg, 0.89 mmol),3-chlorobenzamide (210 mg, 1.3 mmol), K₃PO₄ (570 mg, 2.7 mmol),JackiePhos Pd G3 (120 mg, 0.100 mmol) and t-BuOH (4 ml). The mixture wasevacuated and backfilled with N₂ (4 times), then heated to 110° C. for2.5 h. After 2.5 h the reaction mixture was filtered and purified underPurification A conditions to afford methyl1-(4-(3-chlorobenzamido)phenyl)-3-hydroxycyclobutanecarboxylate. MS(ESI) Calc'd [M+H]⁺, 360; found, 360.

Step 2: Preparation of methyl1-(4-(3-chlorobenzamido)phenyl)-3-fluorocyclobutane-1-carboxylate

To a solution of methyl1-(4-(3-chlorobenzamido)phenyl)-3-hydroxycyclobutanecarboxylate (40 mg,0.11 mmol) in DCM (800 μl) and DIEA (50 μl, 0.29 mmol), was added asolution of diethylaminosulfur trifluoride (27 mg, 0.17 mmol) in DCM(200 μl) at 0° C. The mixture was warmed to RT and stirred at RT for 24h. After 24 h the mixture was cooled to 0° C. and DAST (16 μl, 0.12mmol) in DCM (200 ul) was added. After stirring at RT for 20 h,saturated NaHCO₃ was added and the mixture was washed with DCM. Theorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified on silica gel (25 g flash column, EtOAc in hexane, 0-50%, 15CV) to afford methyl1-(4-(3-chlorobenzamido)phenyl)-3-fluorocyclobutanecarboxylate. MS (ESI)Calc'd [M+H]⁺, 362; found, 362.

Step 3: Preparation of1-(4-(3-chlorobenzamido)phenyl)-3-fluorocyclobutane-1-carboxylic Acid

To a vial containing methyl1-(4-(3-chlorobenzamido)phenyl)-3-fluorocyclobutanecarboxylate (14 mg,0.039 mmol) was added THF (300 μl), MeOH (100 μl) and NaOH (100 μl,0.100 mmol, 1M). The mixture was stirred at RT for 18 h. After 18 h thereaction mixture was concentrated under reduced pressure. To theresulting aqueous solution, was added HCl (1M) to adjust the pH to ˜3.The reaction mixture was concentrated under reduced pressure to afford1-(4-(3-chlorobenzamido)phenyl)-3-fluorocyclobutane-1-carboxylic acid.MS (ESI) Calc'd [M+H]⁺, 348; found, 348.

Step 4: Preparation of3-chloro-N-(4-(3-fluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide(Compound 62)

To a vial was added1-(4-(3-chlorobenzamido)phenyl)-3-fluorocyclobutanecarboxylic acid (13mg, 0.037 mmol), HATU (21 mg, 0.056 mmol), DMF (400 μl), 4-fluoroaniline(21 mg, 0.19 mmol) and DIEA (50 μl, 0.29 mmol). The mixture was stirredat RT for 2 h. After 2 h the mixture was filtered and purified underPurification A conditions to afford the title compound. MS (ESI) Calc'd[M+H]⁺, 441; found, 441. ¹H NMR (600 MHz, DMSO-d₆) δ 10.32 (s, 1H), 9.52(s, 1H), 7.95 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H),7.62 (d, J=7.8 Hz, 1H), 7.57-7.41 (m, 3H), 7.35 (d, J=8.4 Hz, 2H), 7.07(t, J=8.8 Hz, 2H), 5.07 (dq, J=56.0, 6.7 Hz, 1H), 3.39-3.17 (m, 2H),2.64-2.45 (m, 2H).

Example 63: Preparation of3-chloro-N-(4-(3,3-difluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of methyl1-(4-chlorophenyl)-3,3-difluorocyclobutane-1-carboxylate

To a solution of methyl 1-(4-chlorophenyl)-3-oxocyclobutanecarboxylate(0.49 g, 2.0 mmol) in DCM (10 ml), was added a solution of DAST (0.6 ml,4.5 mmol) in DCM (2 ml) at 0° C. The mixture was warmed to RT andstirred at RT for 16 h. After 16 h saturated NaHCO₃ was added and themixture was washed with DCM. The organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified on silica gel chromatography (12 gflash column, EtOAc in hexane, 0-10%, 15 CV) to afford methyl1-(4-chlorophenyl)-3,3-difluorocyclobutanecarboxylate.

Step 2: Preparation of methyl1-(4-aminophenyl)-3,3-difluorocyclobutane-1-carboxylate

To a vial was added methyl1-(4-chlorophenyl)-3,3-difluorocyclobutanecarboxylate (95 mg, 0.36mmol), Pd₂(dba)₃ (42 mg, 0.046 mmol), and Toluene (1500 μl). The mixturewas evacuated and back filled with N₂ (3 times). Tri-tert-butylphosphine10% weight in hexane (97 mg, 0.048 mmol) and LiHMDS (500 μl, 0.500 mmol)were added to the reaction vial. The mixture was evacuated and backfilled with N₂ (3 times). The resulting solution was stirred at RT for17 h. After 17 h the mixture was diluted with Et₂O (2 ml), and thesilylamide was deprotected by adding 1 drop of 1 N HCl. The mixture waswashed with 1N NaOH. The organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified on silica gel chromatography (12 g flashcolumn, 0-50%, 15 C V; 50-50%, 5 CV) to afford methyl1-(4-aminophenyl)-3,3-difluorocyclobutanecarboxylate. MS (ESI) Calc'd[M+H]⁺, 242; found, 242.

Step 3: Preparation of methyl1-(4-(3-chlorobenzamido)phenyl)-3,3-difluorocyclobutane-1-carboxylate

Methyl 1-(4-aminophenyl)-3,3-difluorocyclobutanecarboxylate (74 mg, 0.31mmol) was dissolved in DCM (1500 μl) and cooled to 0° C. using an icebath. Et₃N (70 μl, 0.50 mmol) and 3-chlorobenzoyl chloride (50 μl, 0.39mmol) were added to the solution drop wise at 0° C. The mixture wasstirred at RT for 18 h. After 18 h the reaction mixture was concentratedunder reduced pressure. The residue was purified on silica gelchromatography (12 g flash column, EtOAc in hexane, 0-20%, 5 CV; 20-20%,10 CV) to afford methyl1-(4-(3-chlorobenzamido)phenyl)-3,3-difluorocyclobutanecarboxylate. MS(ESI) Calc'd [M+H]⁺, 380; found, 380.

Step 4: Preparation of1-(4-(3-chlorobenzamido)phenyl)-3,3-difluorocyclobutane-1-carboxylicAcid

To the vial containing methyl1-(4-(3-chlorobenzamido)phenyl)-3,3-difluorocyclobutanecarboxylate (75mg, 0.20 mmol) was added THF (1.5 ml). To this solution was added NaOH(500 μl, 0.500 mmol), followed by MeOH (0.5 ml). The mixture was stirredat RT for 3 h. After 3 h the reaction mixture was concentrated underreduced pressure. The resulting aqueous solution was acidified to pH ˜2by drop wise addition of HCl (1 M). The resulting solution was washedwith EtOAc 3 times. The combined organics were dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to afford1-(4-(3-chlorobenzamido)phenyl)-3,3-difluorocyclobutane-1-carboxylicacid. MS (ESI) Calc'd [M+H]⁺, 366; found, 366.

Step 5: Preparation of3-chloro-N-(4-(3,3-difluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide(Compound 63)

To a vial was added1-(4-(3-chlorobenzamido)phenyl)-3,3-difluorocyclobutanecarboxylic acid(36 mg, 0.098 mmol), 4-fluoroaniline (28 mg, 0.25 mmol), HATU (45 mg,0.12 mmol), DMF (800 μl) and DIEA (60 μl, 0.34 mmol). The mixture wasstirred at RT for 18 h. After 18 h the mixture was filtered and purifiedunder Purification A conditions to afford the title compound. MS (ESI)Calc'd [M+H]⁺, 459; found, 459. ¹H NMR (600 MHz, DMSO-d₆) δ 10.34 (s,1H), 9.73 (s, 1H), 7.95 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.4Hz, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.58-7.49 (m, 3H), 7.44 (d, J=8.4 Hz,2H), 7.08 (t, J=8.7 Hz, 2H), 3.63-3.29 (m, 2H), 3.08 (q, J=13.0 Hz, 2H).

Examples 65 and 69 in Table 6 were prepared in an analogous way toExample 63, using the corresponding amines in Step 5.

Examples 64 and 66-68 in Table 6 were prepared in an analogous fashionto Example 63, with the corresponding amines in step 5.

Preparative resolution of3-chloro-N-(4-(1-((2-ethoxycyclopropyl)carbamoyl)-3,3-difluorocyclobutyl)phenyl)benzamidewas performed using supercritical fluid chromatography on a BergerMultigram II preparative SFC. A Chiralcel OD-H column (5 μm, 21 mm×250mm, Chiral Technologies Inc., West Chester, Pa.) was used as the chiralstationary phase. The compound mixture was dissolved in methanol.Injection and collection were carried out using the following isocraticSFC conditions: 80% carbon dioxide and 20% methanol with 0.25%dimethylethyl amine as the mobile phase, 220 nm UV wavelength, 100 baroutlet pressure, 35° C. column compartment temperature, 70 mL/min totalflow rate. Retention times for peak collection were as follows: Compound68, 3.6 min; Compound 67, 5.1 min, Compound 64, 6.3 min, Compound 66,7.9 min.

TABLE 6 Ex. # Structure Chemical Name Mass [M + H]+ 64

3-chloro-N-[4-(1-{[(1S,2R)- 2- ethoxycyclopropyl] carbamoyl}-3,3-difluorocyclobutyl)phenyl] benzamide 449 65

3-chloro-N-(4-{Ha- ethoxycyclopropyl)carbamoyl]- 3,3-difluorocyclobutyl}phenyl) benzamide 449 66

3-chloro-N-[4-(1-{[(1R,2S)- 2- ethoxycyclopropyl] carbamoyl}-3,3-difluorocyclobutyl)phenyl] benzamide 449 67

3-chloro-N-[4-(1-{[(lS,2S)- 2- ethoxycyclopropyl] carbamoyl}-3,3-difluorocyclobutyl)phenyl] benzamide 449 68

3-chloro-N-[4-(1-{[(1R,2R)- 2- ethoxycyclopropyl] carbamoyl}-3,3-difluorocyclobutyl)phenyl] benzamide 449 69

3-chloro-N-(4-{3,3-difluoro- 1-[(3,3,3- trifluoropropyl)carbamoyl]cyclobutyl}phenyl) benzamide 461

Example 70:3-Chloro-N-(4-((cis)-1-((4-fluorophenyl)carbamoyl)-3-hydroxycyclobutyl)phenyl)benzamide

Step 1: Preparation of(cis)-1-(4-bromophenyl)-N-(4-fluorophenol)-3-hydroxycyclobutane-1-carboxamide

To a vial was added(cis)-1-(4-bromophenyl)-3-hydroxycyclobutanecarboxylic acid (100 mg,0.37 mmol), HATU (170 mg, 0.44 mmol), DMF (2500 μl), 4-fluoroaniline (45mg, 0.41 mmol) and DIEA (200 μl, 1.1 mmol). The mixture was stirred atRT for 18 h. After 18 h the solvent was concentrated under reducedpressure. The residue was purified by flash chromatography on silica (12g, EtOAc in hexane, 0-80%, 10 CV) to afford(cis)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-hydroxycyclobutanecarboxamide.MS (ESI) Calc'd [M+H]⁺, 364; found, 364.

Step 2: Preparation of3-chloro-N-(4-((cis)-1-((4-fluorophenyl)carbamoyl)-3-hydroxycyclobutyl)phenyl)benzamide

To a vial was added(cis)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-hydroxycyclobutanecarboxamide(39 mg, 0.11 mmol), 3-chlorobenzamide (25 mg, 0.16 mmol), K₃PO₄ (70 mg,0.33 mmol), JackiePhos Pd G3 (12 mg, 11 μmol) and t-BuOH (700 μl). Themixture was evacuated and backfilled with N₂ (4 times), then heated at100° C. for 3 h. After 3 h the mixture was filtered and purified underPurification A conditions to afford the title compound. MS (ESI) Calc'd[M+H]⁺, 439; found, 439. ¹H NMR (600 MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.30(s, 1H), 7.95 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H),7.62 (d, J=7.8 Hz, 1H), 7.58-7.49 (m, 3H), 7.44 (d, J=8.4 Hz, 2H), 7.05(t, J=8.8 Hz, 2H), 3.87 (p, J=7.2 Hz, 1H), 3.33 (s, 1H), 2.86-2.73 (m,2H), 2.54-2.43 (m, 2H).

Example 71:3-Chloro-N-(4-((1r,3r)-1-((4-fluorophenyl)carbamoyl)-3-hydroxy-3-methylcyclobutyl)phenyl)benzamide

Step 1: Preparation of(1r,3r)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-hydroxy-3-methylcyclobutane-1-carboxamide

To a vial was added(1R,3R)-1-(4-bromophenyl)-3-hydroxy-3-methylcyclobutanecarboxylic acid(120 mg, 0.41 mmol), HATU (200 mg, 0.52 mmol), DMF (2.5 ml),4-fluoroaniline (50 mg, 0.45 mmol) and DIEA (250 μl, 1.4 mmol). Themixture was stirred at RT for 18 h. After 18 h the reaction mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica (12 g, EtOAc in hexane, 0-60%, 10 CV) to afford(1R,3R)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-hydroxy-3-methylcyclobutanecarboxamide.MS (ESI) Calc'd [M+H]⁺, 378; found, 378.

Step 2: Preparation of 3-chloro-N-(4-((1r,3r)-1-((4-fluorophenyl)carbamoyl)-3-hydroxy-3-methylcyclobutyl)phenyl)benzamide

To a vial was added(1r,3r)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-hydroxy-3-methylcyclobutanecarboxamide(38 mg, 0.10 mmol), 3-chlorobenzamide (24 mg, 0.15 mmol), K₃PO₄ (65 mg,0.31 mmol), JackiePhos Pd G3 (12 mg, 10 μmol) and t-BuOH (1000 μl). Themixture was evacuated and backfilled with N₂ (4 times), then heated at100° C. for 3.5 h. After 3.5 h the mixture was filtered and purifiedunder Purification A conditions to afford the title compound. MS (ESI)Calc'd [M+H]⁺, 453; found, 453. ¹H NMR (600 MHz, DMSO-d₆) δ 10.28 (s,1H), 9.55 (s, 1H), 7.95 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.58-7.48 (m, 3H), 7.33 (d, J=8.4 Hz,2H), 7.06 (t, J=8.7 Hz, 2H), 3.38 (s, 1H), 2.96 (d, J=12.2 Hz, 2H),2.51-2.37 (m, 2H), 1.17 (s, 3H).

Example 72:N-(4-(3,3-Difluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)-3-fluorobenzamide

Step 1: Preparation of1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile

To a suspension of NaH (4.1 g, 100 mmol) (60% in mineral oil) in DMF(100 mL) was added 2-(4-bromophenyl)acetonitrile (10 g, 51 mmol)followed by 1,3-dibromo-2,2-dimethoxypropane (11 g, 42 mmol). Thereaction mixture was heated to 60° C. for 12 h. After 12 h the reactionmixture was diluted with water (1000 mL) and washed with EtOAc (400mL×2). The combined organics were washed with brine (100 mL), dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica (petroleumether:EtOAc=50:1 to 20:1) to afford1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile. MS (ESI) Calc'd[M+H]⁺, 296; found, 296.

Step 2: Preparation of1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarboxylic Acid

To a solution of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile(15.11 g, 51.0 mmol) in EtOH (20 mL) was added NaOH (5.54 g, 137 mmol)and water (5 mL) while stirring at RT. The reaction mixture was heatedto 85° C. for 36 h. After 36 h the reaction mixture was concentratedunder reduced pressure. The residue was diluted with water (150 mL) andwashed with EtOAc (50 mL×3). The combined organics were washed withbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarboxamide.

Step 3: Preparation of methyl1-(4-bromophenyl)-3-oxocyclobutanecarboxylate

To a solution of 1-(4-bromophenyl)-3,3-dimethoxycyclobutanecarboxylicacid (2.5 g, 8.0 mmol) in MeOH (30 mL) was added H₂SO₄ (2.0 mL, 38 mmol)while stirring at RT. The reaction mixture was stirred for 14 h. After14 h the reaction mixture was concentrated under reduced pressure. Theresidue was diluted with water (30 mL) and washed with EtOAc (30 mL×3).The combined organics were washed with brine (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (petroleum ether:EtOAc30:1-10:1 as eluent) to afford methyl1-(4-bromophenyl)-3-oxocyclobutanecarboxylate.

Step 4: Preparation of methyl1-(4-bromophenyl)-3,3-difluorocyclobutanecarboxylate

To a solution of methyl 1-(4-bromophenyl)-3-oxocyclobutanecarboxylate(1.5 g, 5.4 mmol) in DCM (15 mL) was added DAST (1.4 mL, 11 mmol) whilestirring at 0° C. under N₂. The reaction mixture was stirred at 0° C.while warming to RT for 15 h. After 15 h saturated NaHCO₃ (20 mL) wasadded slowly. The mixture was washed with DCM (30 mL×3). The combinedorganics were washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (SiO₂) using (petroleumether:EtOAc 50:1-30:1 as eluent) to afford methyl1-(4-bromophenyl)-3,3-difluorocyclobutanecarboxylate.

Step 5: Preparation of methyl3,3-difluoro-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutane-1-carboxylate

To a solution of methyl1-(4-bromophenyl)-3,3-difluorocyclobutanecarboxylate (800 mg, 2.6 mmol)and (4-methoxyphenyl)methanamine (430 mg, 3.2 mmol) in dioxane (10 mL)was added Cs₂CO₃ (2600 mg, 7.9 mmol) and XPhos precatalyst (190 mg, 0.26mmol) while stirring at RT under N₂ atmosphere. The reaction mixture wasstirred 100° C. for 14 h. After 14 h the reaction mixture was dilutedwith water (20 mL), then washed with EtOAc (30 mL×3). The combinedorganics were washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (petroleum ether:EtOAc30:1-5:1) to afford methyl3,3-difluoro-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxylate.

Step 6: Preparation of 3,3-difluoro-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxylic Acid

To a solution of methyl3,3-difluoro-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxylate(950 mg, 2.6 mmol) in THF (2.0 ml)/MeOH (2.0 ml)/water (1.0 mL) wasadded lithium hydroxide hydrate (440 mg, 11 mmol) while stirring at RT.The reaction was allowed to stir at RT for 14 h. After 14 h the reactionmixture was diluted with water (10 mL) and 1N HCl was added drop wise toreach pH ˜3. The combined organics were concentrated under reducedpressure. The residue was washed with EtOAc (20 mL×2). The combinedorganics were washed with brine (20 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure to afford3,3-difluoro-1-(4-((4-methoxybenzyl)amino) phenyl)cyclobutanecarboxylicacid. MS (ESI) Calc'd [M+H]⁺, 348; found, 348.

Step 7: Preparation of3,3-difluoro-N-(4-fluorophenyl)-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxamide

To a solution of3,3-difluoro-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxylicacid (860 mg, 2.5 mmol) and 4-fluoroaniline (300 mg, 2.7 mmol) in DCM(5.0 mL) was added HATU (940 mg, 2.5 mmol) and DIEA (1.3 ml, 7.4 mmol)while stirring at RT. The reaction mixture was stirred for 1 h. After 1h the reaction mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (petroleumether:EtOAc 20:1-5:1) to afford3,3-difluoro-N-(4-fluorophenyl)-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxamide.MS (ESI) Calc'd [M+H]⁺, 441; found, 463 (M+Na⁺).

Step 8: Preparation of1-(4-aminophenyl)-3,3-difluoro-N-(4-fluorophenyl)cyclobutanecarboxamide

To a solution of3,3-difluoro-N-(4-fluorophenyl)-1-(4-((4-methoxybenzyl)amino)phenyl)cyclobutanecarboxamide(460 mg, 1.04 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 0.094 mmol)(10%) while stirring at RT under N₂ atmosphere. The reaction mixture wasstirred at RT under H₂ (15 PSI) for 5 h. After 5 h the reaction mixturewas filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (petroleum ether:EtOAc5:1-2:1) to afford1-(4-aminophenyl)-3,3-difluoro-N-(4-fluorophenyl)cyclobutanecarboxamide.MS (ESI) Calc'd [M+H]⁺, 321; found, 321.

Step 9: Preparation ofN-(4-(3,3-difluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)-phenyl)-3-fluorobenzamide

To a solution of1-(4-aminophenyl)-3,3-difluoro-N-(4-fluorophenyl)cyclobutanecarboxamide(30 mg, 0.094 mmol) and 3-fluorobenzoic acid (13 mg, 0.094 mmol) inpyridine (2.0 mL) was added POCl₃ (0.474 mL, 5.09 mmol) while stirringat 0° C. The reaction mixture was stirred at 0° C. for 1 h. After 1 h,water (3 mL) was added and the mixture was concentrated under reducedpressure. The residue was purified under Purification A conditions toafford the title compound. MS (ESI) Calc'd [M+H]⁺, 443; found, 443. ¹HNMR (400 MHz, CD₃OD) δ 7.71-7.80 (m, 3H), 7.68 (br d, J=9.7 Hz, 1H),7.43-7.58 (m, 5H), 7.29-7.38 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 3.43-3.56(m, 2H), 3.13 (q, J=13.1 Hz, 2H).

Examples 73-76 in Table 7 were prepared in an analogous way to Example72, using the corresponding carboxylic acids in Step 9.

TABLE 7 Ex. # Structure Chemical Name Mass [M + H]+ 73

3-cyano-N-(4-{3,3- difluoro-1-[(4- fluorophenyl)carbamoyl]cyclobutyl}phenyl) benzamide 450 74

4-chloro-N-(4-{3,3- difluoro-1-[(4- fluorophenyl)carbamoyl]cyclobutyl}phenyl) pyridine-2-carboxamide 460 75

5-chloro-N-(4-{3,3- difluoro-1-[(4- fluorophenyl)carbamoyl]cyclobutyl}phenyl) pyridine-3-carboxamide 460 76

N-(4-{3,3-difluoro-1-[(4- fluorophenyl)carbamoyl] cyclobutyl}phenyl)-2-(trifluoromethyl) pyridine-4-carboxamide 494

Example 77:4-Fluoro-3-methyl-N-(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of 1-(4-nitrophenyl)cyclobutanecarbonitrile

To a solution of 2-(4-nitrophenyl)acetonitrile (14 g, 89 mmol) and K₂CO₃(32 g, 230 mmol) in acetone (160 mL) was added 1,3-dibromopropane (22 g,110 mmol). The solution was heated to 65° C. and stirred for 18 h. After18 h the reaction mixture was filtered and concentrated under reducedpressure. Saturated NH₄Cl solution (200 mL) was added and the mixturewas washed with EtOAc (200 mL). The combined organics were concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (Petroleum ether:EtOAc=30:1 to 5:1) to afford1-(4-nitrophenyl)cyclobutane-carbonitrile.

Step 2: Preparation of 1-(4-nitrophenyl)cyclobutanecarboxylic Acid

To a solution of 1-(4-nitrophenyl)cyclobutanecarbonitrile (1.5 g, 7.4mmol) in EtOH (30 ml)/H₂O (10 ml) was added KOH (4.2 g, 74 mmol). Thereaction mixture was stirred while refluxing for 24 h. After 24 h thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in water (50 mL) and the aqueous solution was washed withEtOAc (40 mL×2). The pH of the aqueous mixture was adjusted to ˜2.0(with drop wise addition of 3 M HCl) and was washed with EtOAc (50mL×2). The combined organics were washed with brine (25 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford 1-(4-nitrophenyl)cyclobutanecarboxylic acid.

Step 3: Preparation of 1-(4-nitrophenyl)cyclobutanecarbonyl Chloride

To a solution of 1-(4-nitrophenyl)cyclobutanecarboxylic acid (900 mg,4.1 mmol) in DCM (20 ml) was added oxalyl dichloride (1030 mg, 8.1 mmol)at 0° C., drop wise. The mixture was stirred at RT for 2 h. After 2 hthe reaction mixture was concentrated under reduced pressure to afford1-(4-nitrophenyl)cyclobutanecarbonyl chloride.

Step 4: Preparation of 1-(4-nitrophenyl)-N-propylcyclobutanecarboxamide

To a solution of propan-1-amine (330 mg, 5.6 mmol) and Et₃N (1.6 ml, 11mmol) in DCM (15 mL) was added a solution of1-(4-nitrophenyl)cyclobutanecarbonyl chloride (900 mg, 3.8 mmol) in DCM(5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. After1 h the reaction mixture was diluted with DCM (50 mL) and washed withaqueous 1.0 M HCl (20 mL×2). The resulting organics were washed withsaturated NaHCO₃ (20 mL), and brine (20 mL). The combined organics weredried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford1-(4-nitrophenyl)-N-propylcyclobutanecarboxamide. MS (ESI) Calc'd[M+H]⁺, 263; found, 263.

Step 5: Preparation of 1-(4-aminophenyl)-N-propylcyclobutanecarboxamide(Intermediate 5)

To a solution of 1-(4-nitrophenyl)-N-propylcyclobutanecarboxamide (900mg, 3.43 mmol) in EtOAc (30 ml) was added Pd/C (100 mg, 0.094 mmol). Thereaction mixture was stirred under 15 PSI H₂ at RT for 1 h. After 1 hthe reaction mixture was filtered and the filter cake was washed withEtOAc (100 mL). The combined filtrate was concentrated under reducedpressure to afford 1-(4-aminophenyl)-N-propylcyclobutanecarboxamide. MS(ESI) Calc'd [M+H]⁺, 233; found, 233.

Step 6: Preparation of4-fluoro-3-methyl-N-(4-(1-(propylcarbamoyl)cyclobutyl)phenyl) benzamide

To a solution of 1-(4-aminophenyl)-N-propylcyclobutanecarboxamide (100mg, 0.43 mmol) (Intermediate 5) and TEA (0.180 ml, 1.29 mmol) in DCM (5mL) was added 4-fluoro-3-methylbenzoyl chloride (150 mg, 0.86 mmol) inDCM (2 mL) while stirring at 0° C. The reaction mixture was stirred at0° C. for 1 h. After 1 h the reaction mixture was diluted with water(100 mL) and washed with EtOAc (50 mL×2). The combined organics werewashed with aqueous NaHCO₃ (100 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified under Purification C conditions to afford the title compound.MS (ESI) Calc'd [M+H]⁺, 369; found, 369. ¹H NMR (400 MHz, DMSO-d₆) δ10.2 (s, 1H), 7.9 (dd, J=7.5, 1.8 Hz, 1H), 7.8-7.9 (m, 1H), 7.7 (d,J=8.7 Hz, 2H), 7.5 (t, J=5.8 Hz, 1H), 7.3-7.3 (m, 3H), 3.0 (q, J=6.7 Hz,2H), 2.7 (dq, J=8.3, 6.1 Hz, 2H), 2.3-2.4 (m, 5H), 1.7-1.9 (m, 2H), 1.3(sxt, J=7.2 Hz, 2H), 0.7 (t, J=7.4 Hz, 3H).

Examples 78-81 in Table 8 were prepared in an analogous way to Example77, using the corresponding acid chloride in Step 6.

TABLE 8 Ex. # Structure Chemical Name Mass [M + H]+ 78

3-chloro-4-fluoro-N-{4-[1- (propylcarbamoyI)cyclobutyl] phenyl}benzamide389 79

3-chloro-5-fluoro-N-{4-[1- (propylcarbamoyl)cyclobutyl] phenyl}benzamide389 80

3,5-dichloro-N-{4-[1- (propylcarbamoyl)cyclobutyl] phenyl}benzamide 40581

3,4-dichloro-N-{4-[1- (propylcarbamoyl)cyclobutyl] phenyl}benzamide 405

Example 82:3-Chloro-N-(2-fluoro-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of 4-bromo-2-fluoroaniline

To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.5mmol) in EtOH (50 mL)/Water (20 mL) was added iron (12.7 g, 230 mmol)and NH₄Cl (24.3 g, 455 mmol). The reaction mixture was stirred at 90° C.for 2 h. After 2 h the reaction mixture was filtered over Celite. Thefilter cake was washed with EtOH (300 mL), and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (SiO₂, Petroleum ether/EtOAc=10:1 to 5:1) to afford4-bromo-2-fluoroaniline.

Step 2: Preparation of N-(4-bromo-2-fluorophenyl)-3-chlorobenzamide

To a solution of 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) and TEA (2.20mL, 15.79 mmol) in DCM (15 mL) was added 3-chlorobenzoyl chloride (1.84g, 10.53 mmol) in DCM (2 mL). The mixture was stirred at 0° C. for 1 h.After 1 h the reaction mixture was diluted with water (100 mL) andwashed with EtOAc (50 mL×2). The combined organics were washed withaqueous saturated NaHCO₃ (100 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (SiO₂, Petroleum ether:EtOAc=10:1to 5:1) to afford N-(4-bromo-2-fluorophenyl)-3-chlorobenzamide.

Step 3: Preparation of3-chloro-N-(4-(1-cyanocyclobutyl)-2-fluorophenyl)benzamide

To a solution of N-(4-bromo-2-fluorophenyl)-3-chlorobenzamide (350 mg,1.07 mmol) in THF (15 mL) was added DPPF (59 mg, 0.11 mmol), Pd₂(dba)₃(49 mg, 0.054 mmol) and cyclobutanecarbonitrile (173 mg, 2.13 mmol).LiHMDS (2.13 ml, 2.13 mmol) was added. The reaction mixture was stirredat 80° C. for 16 h. After 16 h, aqueous NH₄Cl (20 mL) was added to thereaction mixture, and the reaction mixture was washed with EtOAc (10mL×5). The combined organics were washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by Prep-TLC using (SiO₂, petroleum ether:EtOAc=5:1)to afford 3-chloro-N-(4-(1-cyanocyclobutyl)-2-fluorophenyl)benzamide. MS(ESI) Calc'd [M+H]⁺, 329; found, 329.

Step 4: Preparation ofN-(4-(1-carbamoylcyclobutyl)-2-fluorophenyl)-3-chlorobenzamide

To a stirred solution of3-chloro-N-(4-(1-cyanocyclobutyl)-2-fluorophenyl)benzamide (38 mg, 0.12mmol) in AcOH (1 mL) was added H₂SO₄ (12 mg, 0.12 mmol) at 0° C. Thereaction mixture was stirred at 90° C. for 16 h. After 16 h the pH wasadjusted to pH ˜9 by addition of 2 N NaOH (20 mL). The reaction mixturewas washed with ethyl acetate (20 mL×3) and the combined organics werewashed with brine (5 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to affordN-(4-(1-carbamoylcyclobutyl)-2-fluorophenyl)-3-chlorobenzamide. MS (ESI)Calc'd [M+H]⁺, 347; found, 347.

Step 5: Preparation of1-(4-(3-chlorobenzamido)-3-fluorophenyl)cyclobutanecarboxylic Acid

To a solution ofN-(4-(1-carbamoylcyclobutyl)-2-fluorophenyl)-3-chlorobenzamide (20 mg,0.058 mmol) in ethanol (2 mL) was added NaOH (28 mg, 0.700 mmol) whilestirring at RT. The reaction was heated to 90° C. and the reactionmixture was stirred for 24 h. After 24 h the reaction mixture wasacidified to pH-2 with 1 M HCl (2 mL). The mixture was washed with EtOAc(30 mL×3) and the combined organics were washed with brine (30 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified under Purification B conditions to afford1-(4-(3-chlorobenzamido)-3-fluorophenyl)cyclobutanecarboxylic acid. MS(ESI) Calc'd [M+H]⁺, 348; found, 348.

Step 6: Preparation of3-chloro-N-(2-fluoro-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide

To a solution of1-(4-(3-chlorobenzamido)-3-fluorophenyl)cyclobutanecarboxylic acid (30mg, 0.086 mmol) and HATU (33 mg, 0.087 mmol) in DMF (1 mL) was added3,3,3-trifluoropropan-1-amine (10 mg, 0.088 mmol) and DIEA (0.045 mL,0.255 mmol) while stirring at RT. The reaction was stirred at RT for 18h. After 18 h the reaction mixture was purified under Purification Bconditions to afford the title compound. MS (ESI) Calc'd [M+H]⁺, 348;found, 348. ¹H NMR (400 MHz, CD₃OD) δ 8.0 (s, 1H), 7.9 (br d, J=7.5 Hz,1H), 7.7 (t, J=8.1 Hz, 1H), 7.6 (br d, J=7.9 Hz, 1H), 7.5-7.5 (m, 1H),7.2-7.3 (m, 2H), 3.4-3.4 (m, 2H), 2.8 (s, 2H), 2.5 (br d, J=7.5 Hz, 2H),2.3-2.4 (m, 2H), 1.9 (br s, 2H).

Example 83:3-Chloro-N-(2-(hydroxymethyl)-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate

To a solution of ethyl 2-(4-nitrophenyl)acetate (3 g, 14.34 mmol) in DMF(60 mL) was added NaH (1.20 g, 30.1 mmol) (60% in oil) while stirring at0° C. The reaction mixture was allowed to warm to RT and was stirred for15 min. After 15 min the mixture was cooled to 0° C. and1,3-diiodopropane (3.4 mL, 29.6 mmol) was added. The resulting mixturewas stirred at 0° C. for 30 min, then warmed to RT and stirred for 1 h.After 1 h the reaction mixture was diluted with aqueous NH₄Cl (60 mL)and was washed with EtOAc (30 mL×3). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (Petroleum ether/EtOAc=100:1 to 50:1) to afford ethyl1-(4-nitrophenyl)cyclobutanecarboxylate.

Step 2: Preparation of ethyl 1-(4-aminophenyl)cyclobutanecarboxylate

To a solution of ethyl 1-(4-nitrophenyl)cyclobutanecarboxylate (1.65 g,6.62 mmol) in EtOH (27 mL)/Water (3 mL) was added ammonium chloride(3.54 g, 66.2 mmol) and iron (1.9 g, 34.0 mmol) while stirring at RT.The reaction mixture was stirred at 90° C. for 2 h. After 2 h thereaction mixture was filtered and concentrated under reduced pressure.The residue was diluted with water (30 mL) and washed with EtOAc (20mL×3). The combined organics were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (SiO₂, Petroleum ether/EtOAc=5:1)to afford ethyl 1-(4-aminophenyl)cyclobutanecarboxylate. MS (ESI) Calc'd[M+H]⁺, 220; found, 220.

Step 3: Preparation of ethyl1-(4-amino-3-bromophenyl)cyclobutanecarboxylate

To a solution of ethyl 1-(4-aminophenyl)cyclobutanecarboxylate (0.5 g,2.28 mmol) in DMF (10 mL) was added NBS (0.37 g, 2.08 mmol) whilestirring at −10° C. The reaction mixture was stirred −10° C. for 2 h.After 2 h the reaction mixture was diluted with water (5 mL) and washedwith EtOAc (5 mL×3). The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (SiO₂, Petroleumether/EtOAc=40:1 to 20:1) to afford ethyl1-(4-amino-3-bromophenyl)cyclobutanecarboxylate. MS (ESI) Calc'd [M+H]⁺,298; found, 298.

Step 4: Preparation of 3-chlorobenzoyl Chloride (Intermediate 6)

To a solution of 3-chlorobenzoic acid (0.4 g, 2.55 mmol) in DCM (2 mL)was added DMF (0.05 g, 0.68 mmol) and oxalyl dichloride (0.44 mL, 5.13mmol) while stirring at 0° C. The reaction mixture was stirred at 20° C.for 2 h, then concentrated under reduced pressure to afford3-chlorobenzoyl chloride.

Step 5: Preparation of ethyl1-(3-bromo-4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate

To a solution of ethyl 1-(4-amino-3-bromophenyl)cyclobutanecarboxylate(0.46 g, 1.54 mmol) and TEA (0.47 g, 4.63 mmol) in DCM (5 mL) was added3-chlorobenzoyl chloride (0.27 g, 1.543 mmol) (Intermediate 6) in DCM (3mL) while stirring at 0° C. The reaction mixture was stirred at 0° C.for 3 h. After 3 h the reaction mixture was concentrated under reducedpressure. The residue was purified under Purification D conditions toafford ethyl1-(3-bromo-4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate. MS (ESI)Calc'd [M+H]⁺, 436; found, 438.

Step 6: Preparation of1-(3-bromo-4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylic Acid

To a solution of ethyl1-(3-bromo-4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylate (0.32 g,0.72 mmol) in MeOH (2 mL)/THF (2 mL)/water (1 mL) was added lithiumhydroxide hydrate (0.15 g, 3.61 mmol) while stirring at RT. The reactionmixture was stirred at RT for 15 h. After 15 h the reaction mixture wasdiluted water (20 mL) and acidified with 2.0 M aqueous HCl to pH ˜3.0.The mixture was washed with EtOAc (20 mL×3) and the combined organicswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford1-(3-bromo-4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylic acid. MS(ESI) Calc'd [M+H]⁺, 408; found, 410.

Step 7: Preparation ofN-(2-bromo-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide

To a solution of1-(3-bromo-4-(3-chlorobenzamido)phenyl)cyclobutanecarboxylic acid (270mg, 0.66 mmol) in THF (10 mL) was added HATU (276 mg, 0.73 mmol),3,3,3-trifluoropropan-1-amine (82 mg, 0.73 mmol) and TEA (0.4 mL, 2.87mmol) while stirring at RT. The reaction mixture was stirred at RT for 2h. After 2 h the reaction mixture was poured into water (20 mL) andwashed with EtOAc (20 mL×2). The combined organics were washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (Petroleum ether:EtOAc=20:1 to 5:1) toaffordN-(2-bromo-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide.MS (ESI) Calc'd [M+H]⁺, 503; found, 505.

Step 8: Preparation of(E)-N-(2-((tert-butylimino)methyl)-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide (Intermediate 7)

To a solution ofN-(2-bromo-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide(300 mg, 0.60 mmol) in DMF (6 mL) was added[1,1′-biphenyl]-2-yldi-tert-butylphosphine (8 mg, 0.027 mmol),2-isocyano-2-methylpropane (60 mg, 0.72 mmol), diacetoxypalladium (4 mg,0.018 mmol), triethylsilane (208 mg, 1.79 mmol) and Na₂CO₃ (64 mg, 0.60mmol) while stirring at RT. The reaction mixture was heated to 65° C.and stirred for 10 h. After 10 h the reaction mixture was diluted withwater (60 mL) and washed with EtOAc (20 mL×2). The combined organicswere dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by pre-TLC (petroleumether:EtOAc=2:1) to afford(E)-N-(2-((tert-butylimino)methyl)-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide.MS (ESI) Calc'd [M+H]⁺, 508; found, 508.

Step 9: Preparation of3-chloro-N-(2-formyl-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide

To a solution of(E)-N-(2-((tert-butylimino)methyl)-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)-3-chlorobenzamide(25 mg, 0.049 mmol) (Intermediate 7) in acetonitrile (2 mL)/water (1 mL)was added 3 M hydrogen chloride (0.5 mL, 1.50 mmol) while stirring atRT. The reaction mixture was stirred at RT for 5 h. After 5 h thereaction mixture was concentrated under reduced pressure to afford3-chloro-N-(2-formyl-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide.MS (ESI) Calc'd [M+H]⁺, 453; found, 453.

Step 10: Preparation of3-chloro-N-(2-(hydroxymethyl)-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide

To a solution of3-chloro-N-(2-formyl-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide(22 mg, 0.049 mmol) in MeOH (2 mL) was added NaBH₄ (4 mg, 0.11 mmol)while stirring at RT. The reaction mixture was stirred at RT for 30 min.After 30 min the reaction mixture was concentrated under reducedpressure and purified under Purification B conditions to afford thetitle compound. MS (ESI) Calc'd [M+H]⁺, 455; found, 477 (M+Na⁺). ¹H NMR(400 MHz, CD₃OD) δ 7.96 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.72-7.80 (m,2H), 7.59-7.63 (m, 1H), 7.50-7.55 (m, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.34(dd, J=8.4, 2.2 Hz, 1H), 4.71 (s, 2H), 3.33-3.38 (m, 2H), 2.73-2.81 (m,2H), 2.46-2.54 (m, 2H), 2.32 (qt, J=11.0, 7.0 Hz, 2H), 1.82-1.99 (m,2H).

Examples 84-85 in Table 9 were prepared in an analogous way to Example83. Example 84 was Intermediate 7 formed in the synthesis of Example 83.

TABLE 9 Ex. # Structure Chemical Name Mass [M + H]+ 84

N-(2-[(E)-(tert- butylimino)melhyl]-4-{1- [(3,3,3-trifluoropropyl)carbamoyl] cyclobutyl}phenyl)-3- chlorobenzamide 508 85

3-chloro-N-[4-{1-[(5- fluoropyridin-2- yl)carbamoyl]cyclobutyl}- 2-(hydroxymethyl)phenyl] benzamide 454

Example 86:3-Chloro-N-(4-(1-((4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbamoyl)cyclobutyl)phenyl)benzamide

Step 1: Preparation of N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1-(4-nitrophenyl)cyclobutane-1-carboxamide

To a solution of 1-(4-nitrophenyl)cyclobutanecarboxylic acid (734 mg,3.32 mmol) and DMF (cat, 48 mg) in DCM (20 mL) was added oxalyldichloride (842 mg, 6.64 mmol) drop wise at 0° C. The reaction mixturewas stirred at RT for 2 h. After 2 h the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in DCM(20 mL) and TEA (0.23 ml, 1.70 mmol) was added, followed by the additionof 4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-amine (100 mg, 0.42 mmol)in DCM (5 mL) while stirring at 0° C. The reaction mixture was stirredat 0° C. for 1 h. After 1 h the reaction mixture was diluted with DCM(50 mL) and washed with 1.0 M HCl aqueous solution (20 mL×2). Themixture was washed with saturated NaHCO₃ aqueous solution (20 mL) andbrine (20 mL). The combined organics were dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to affordN-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1-(4-nitrophenyl)cyclobutanecarboxamide. MS (ESI)Calc'd [M+H]⁺, 341; found, 341.

Step 2: Preparation of N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1-(4-nitrophenyl)cyclobutane-1-carboxamide

To a solution of N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1-(4-nitrophenyl)cyclobutanecarboxamide (142 mg,0.42 mmol) in EtOAc (30 mL) was added Pd/C (13 mg, 0.012 mmol) and themixture was subjected to hydrogenation under 15 PSI at 20° C. for 1 h.After 1 h the reaction mixture was filtered over Celite, rinsing withEtOAc (100 mL). The filtrate was concentrated under reduced pressure toafford1-(4-aminophenyl)-N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)cyclobutanecarboxamide.MS (ESI) Calc'd [M+H]⁺, 311; found, 311.

Step 3: Preparation of3-chloro-N-(4-(1-((4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbamoyl)cyclobutyl)phenyl)benzamide

To a solution of1-(4-aminophenyl)-N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)cyclobutanecarboxamide(65 mg, 0.21 mmol) and TEA (0.088 mL, 0.63 mmol) in DCM (5 mL) was addeda solution of 3-chlorobenzoyl chloride (73.3 mg, 0.42 mmol) in DCM (2mL) while stirring at 0° C. The reaction mixture was stirred at 0° C.for 1 h. After 1 h the reaction mixture was diluted with water (50 mL)and washed with EtOAc (25 mL×2). The combined organics were washed withaqueous NaHCO₃ (50 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified underPurification C conditions to afford the title compound. MS (ESI) Calc'd[M+H]⁺, 449; found, 449. ¹H NMR (400 MHz, DMSO-d₆). δ10.3 (s, 1H), 8.3(d, J=7.5 Hz, 1H), 8.0 (s, 1H), 7.9 (d, J=7.9 Hz, 1H), 7.6-7.7 (m, 3H),7.5-7.6 (m, 1H), 7.3 (d, J=8.3 Hz, 2H), 7.1-7.2 (m, 1H), 7.0-7.1 (m,1H), 6.9 (br d, J=7.9 Hz, 1H), 5.2 (br s, 1H), 3.4 (dd, J=13.4, 5.0 Hz,1H), 2.9 (br d, J=14.0 Hz, 1H), 2.6-2.8 (m, 2H), 2.3-2.4 (m, 2H),1.7-1.9 (m, 2H).

Example 87 in Table 10 were prepared from Intermediate 5, following theconditions exemplified in the preparation of Example 86 (Step 3) usingthe corresponding carboxylic acid (bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid).

TABLE 10 Ex. # Structure Chemical Name Mass [M + H]+ 87

N-{4-[1- (propylcarbamoyl)cyclobutyl] phenyl}bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide 363Biological Assays

Exemplary compounds disclosed herein were prepared, and tested todetermine their effect as IDO inhibitors.

IDO1 HEK293 Cellular Assay

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM DMSO stocks. Compound dilutions or DMSO alone werethen dispensed from the dilution plate into a Greiner black 384-wellassay plate (catalog #781086) using an Echo 550 acoustic liquid handler(Labcyte).

HEK293 cell pellets were resuspended to 5×105 cells/mL in completeHEK293 culture media (89% DMEM, 10% FBS, 1% penicillin/streptomycin).Suspended cells (2 mL) were dispensed into each well of a 6-well Corningplate (Catalog #3516). Cells were allowed to attach and were incubatedfor 20 hours at 37° C. in a 5% CO₂ incubator. Flag-IDO1 vector(Genscript True ORF Gold, 2 ug) in 150 uL of Opti-MEM medium was addedto each well of a Corning 24 well plate (Cat #3527) and incubated for 5minutes at room temperature. To each well of the 24-well plate was added150 mL Lipofectamine 2000 (Gibco) and the plate incubated at roomtemperature for 20-30 minutes. To each well of attached cells in the6-well plate, 250 mL of the transfection mix from the 24-well plate wasgently added to each well and IDO1 protein was allowed to express for24-30 hours at 37 degrees Celsius in a 5% CO₂ incubator.

Media was removed from the cells which were then washed with 2 mLDulbecco's phosphate-buffered saline (DPBS). After removal of DPBS, 0.5mL of TrypLE (Gibco) was added and incubated at 5 minutes until cellslift from the surface of the wells. Complete HEK293 culture media (4 mL)was added to each well and cells were collected and pooled into aconical tube. Cells were pelleted at 200×g for 5 minutes and resuspendedin an equal volume of complete DMEM medium. Cells were diluted to 4×105cells per mL in complete HEK293 media. L-Tryptophan was added to give afinal concentration of 200 mM. The diluted transfected cells (50 mL) ornontransfected cells (50 mL) were dispensed into wells of Greiner black384-well assay plates (catalog #781086) containing previously dilutedcompounds. The plate is briefly mixed and centrifuged at 200×g for 10seconds to collect cells at the bottom of the plate. Plates were coveredand incubated for 20-24 hours at 37 degrees C. in a 5% CO₂ incubator.Afterwards 10 mL of 0.5 M methyl isonipecotate in dimethyl sulfoxide wasadded to each well, mixed, sealed, and centrifuged at 500 rpm for 10seconds. Plates were incubated at 37 degrees in a 5% CO₂ incubatorovernight to develop fluoresence. The plates are allowed to cool andthen centrifuged for 1 minute at 1000×g. The resulting fluoresence wasmeasured in an Envision plate reader (Perkin Elmer) with a 400/25 nmexcitation filter and an 510/20 nm emission filter.

The fluoresence intensity of each well was corrected for the backgroundobserved in wells with untransfected cells and was expressed as afraction of the intensity observed in wells of IDO1 transfected cellsand DMSO only. Potencies were calculated by linear least squares fit tothe four parameter logistic IC50 equation.

IDO1 Cellular Assay in Hela Cells Stimulated with IFNγ

Hela cells were cultured in complete Hela culture medium (90% EMEM, 10%heat-inactivated fetal bovine serum) and expanded to about 1×10⁹ cells.The cells were then collected and frozen down at 1×10⁷ cells/vial in 1mL frozen medium (90% complete Hela culture medium, 10% DMSO)

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM DMSO stocks in Echo low volume plate(s). Compounddilutions or DMSO alone were then dispensed from the dilution plate(s)into Greiner black 384-well assay plate(s) (catalog #781086, 50 nL/well)using an Echo 550 acoustic liquid handler (Labcyte).

Frozen Hela cells were thawed and transferred into Hela assay medium(99% complete Hela culture medium, 1% Pen/Strep) with 20 mL medium/vialof cells. The cells were spun down at 250 g in a table top centrifugefor 5 min and suspended in same volume of Hela assay medium. The cellswere then counted and adjusted to a density of 2×10⁵ cells/ml in Helaassay medium. Sterile L-tryptophan were added to the cells with finalconcentration of 300 uM L-tryptophan. A small aliquot (2 mL/plate) ofHela cells were set aside and were not treated with IFNγ, to serve asthe Max-E control. The rest of Hela cells were added with sterile IFNγ(Cat #285-IF, R & D systems) with a final concentration of 100 ng/mL.

Hela cells with and without IFNγ were dispensed to the respective wellsof 384-well assay plates containing the compounds. The plates wereincubated for about 48 hours at a 37° C., 5% CO₂ incubator. Afterwards,12 mL of 0.5 M methyl isonipecotate in dimethyl sulfoxide were addedinto each well and the plates were sealed and incubated at 37° C.without CO₂ overnight. The plates were centrifuged for 1 min at 200×g.The resulting fluorescence was measured in a Spectramax plate reader(Molecular Devices) with a 400 nm excitation filter and a 510 nmemission filter.

The fluorescence intensity of each well was corrected for the backgroundobserved in wells with non-IFNγ-treated cells and was expressed as afraction of the intensity observed in wells of IFNγ-treated cells andDMSO only. Potencies were calculated by linear least squares fit to thefour parameter logistic IC₅₀ equation.

TDO Cellular Assay in Frozen SW48 Cells

SW48 cells were cultured in complete RPMI culture medium (90% RPMI, 10%heat-inactivated fetal bovine serum). When reaching near confluent, thecells were collected and frozen down at 20×106 cells/vial in 1 mL frozenmedium (90% complete RPMI culture medium, 10% DMSO. A2780 cells (withminimal TDO activity) were cultured in complete RPMI culture medium andalso frozen down at 5×106/vial similarly to serve as the Max-E control.

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM DMSO stocks in Echo low volume plate(s). Compounddilutions or DMSO alone were then dispensed from the dilution plate(s)into the Greiner black 384-well assay plate(s) (catalog #781086, 50nL/well) using an Echo 550 acoustic liquid handler (Labcyte) Frozen SW48and A2780 cells were thawed and transferred into RPMI complete assaymedium (99% complete RPMI culture medium, 1% Pen/Strep) with 20 mLmedium/vial of cells. The cells were spun down at 350 g in a table topcentrifuge for 5 minutes and suspended in same volume of RPMI assaymedium. The cells were counted and adjusted to density of 2×105 cells/mlin RPMI assay medium. Sterile L-tryptophan (Sigma, Cat # T0254) wasadded to the cells with final concentration of 300 uM.

SW48 and A2780 cells were dispensed to the respective wells of 384-wellassay plates containing the compounds. The plates were incubated forabout 48 hours at a 37° C., 5% CO₂ incubator. Afterwards, 12 μL of 0.5 Methyl isonipecotate (Sigma Aldrich, Cat # E33505) in dimethyl sulfoxidewere added into each well and the plates were sealed and incubated at37° C. without CO₂ overnight. The plates were centrifuged for 1 minuteat 200×g. The resulting fluorescence was measured in a Spectramax platereader (Molecular Devices) with a 400 nm excitation filter and a 510 nmemission filter.

The fluorescence intensity of each well was corrected for the backgroundobserved in wells with A2780 cells and was expressed as a fraction ofthe intensity observed in wells of SW48 cells and DMSO only. Potencieswere calculated by linear least squares fit to the four parameterlogistic IC₅₀ equation.

The pIC₅₀ values for compounds disclosed herein are shown in thefollowing table:

Ex. Hela IC₅₀ HEK293 IC₅₀ SW48 IC₅₀ Form # (nM) (nM) (nM) Screened 1 48Neutral 2 3 10000 Neutral 3 131 10000 TFA Salt 4 136 10000 TFA Salt 5136 10000 TFA Salt 6 577 10000 TFA Salt 7 4 10000 TFA Salt 8 4 10000Neutral 9 11 10000 TFA Salt 10 14 10000 Neutral 11 19 10000 Neutral 1228 16 585 TFA Salt 13 30 10000 TFA Salt 14 39 23 1211 TFA Salt 15 53 142505 TFA Salt 16 92 10000 TFA Salt 17 108 125 10000 Neutral 18 92 9210000 Neutral 19 2 10000 Neutral 20 2 Neutral 21 7 10000 Neutral 22 3510000 Neutral 23 78 10000 Neutral 24 3 10000 Neutral 25 3 10000 Neutral26 3 10000 Neutral 27 4 10000 TFA Salt 28 4 10000 TFA Salt 29 4 10000TFA Salt 30 5 10000 Neutral 31 8 10000 Neutral 32 12 10000 Neutral 33 1510000 Neutral 34 21 10000 Neutral 35 24 10000 TFA Salt 36 24 10000Neutral 37 28 10000 Neutral 38 31 Neutral 39 34 Neutral 40 39 10000Neutral 41 101 Neutral 42 119 10000 Neutral 43 660 Neutral 44 709 10000Neutral 45 58 10000 Neutral 46 13 Neutral 47 26 Neutral 48 27 Neutral 49126 10000 Neutral 50 151 Neutral 51 404 10000 Neutral 52 427 10000Neutral 53 834 10000 Neutral 54 500 TFA Salt 55 613 TFA Salt 56 923 TFASalt 57 1710 TFA Salt 58 2010 TFA Salt 59 17 10000 TFA Salt 60 489 10000TFA Salt 61 1811 10000 TFA Salt 62 2 10000 Neutral 63 2 10000 Neutral 6437 10000 Neutral 65 71 10000 Neutral 66 89 10000 Neutral 67 207 10000Neutral 68 1435 10000 Neutral 69 56 10000 Neutral 70 32 10000 Neutral 71440 10000 Neutral 72 4 10000 Neutral 73 4 10000 Neutral 74 5 10000Neutral 75 10 10000 Neutral 76 20 7640 Neutral 77 8 10000 Neutral 78 1010000 Neutral 79 11 10000 Neutral 80 12 10000 Neutral 81 13 10000Neutral 82 117 10000 Neutral 83 128 10000 Neutral 84 176 10000 Neutral85 5 10000 Neutral 86 182 10000 Neutral 87 1051 10000 Neutral 88 2 10000NeutralIDO1 Human Whole Blood Assay

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM. 3 mL of compound dilutions or DMSO alone were thendispensed from the dilution plate into a polypropylene 96-well assayplate containing 97 mL of RPMI using an Echo 555 acoustic liquid handler(Labcyte). LPS and IFNγ was prepared in in RPMI to a 10× of final conc.(1000 ng/mL), final concentration is 100 ng/mL.

Human whole blood was drawn in sodium heparin coated tubes from healthyinternal donors. 240 mL of blood was transferred to each of the wells ofa v-bottom 96 well plate. 30 mL of compound was transferred fromintermediate dilution plate, and incubated for 15 min. 30 μL fromstimulants was then transferred to blood and mixed thoroughly. Plate wascovered with breathable membrane and incubated at 37° C. for overnight(18 h).

On day 2 isotope labeled standard of kynurenine and tryptophan was madein water at 10× concentration and 30 mL was added to the blood at 3 mMfinal concentration. The assay plates were centrifuged at 300×G for 10min with no brake to separate plasma from red blood cells. 60 mL ofplasma samples was removed without disturbing red blood cells. Plasmawas diluted with RPMI in 1:1 ratio and proteins were precipitated outwith two volume of Acetonitrile. The plates was centrifuged at 4000×Gfor 60 min. 20 mL of supernatant was carefully transferred to a 384 wellplate contain 40 mL of 0.1% formic acid in water and analyzed byLC/MS/MS.

LC/MS/MS analyses were performed using Thermo Fisher's LX4-TSQ QuantumUltra system. This system consists of four Agilent binaryhigh-performance liquid chromatography (HPLC) pumps and a TSQ QuantumUltra triple quadruple MS/MS instrument. For each sample, 5 mL wereinjected onto an Atlantis T3 column (2.1 mm×150 mm, 3 mm particle size)from Waters. The mobile phase gradient pumped at 0.8 mL/min was used toelute the analytes from the column at 25° C. The elution started at 0% Bincreasing linearly to 25% B at 6.5 min, holding at 25% for 1 min,re-equilibrating to 10 min. Mobile phase A consisted of 0.1% formic acidin water. Mobile phase B consisted of 0.1% of formic acid inacetonitrile. Data was acquired in positive mode using a HESI interface.The operational parameters for the TSQ Quantum Ultra instrument were aspray voltage of 4000 V, capillary temperature of 380° C., vaporizertemperature 400° C., shealth gas 60 arbitrary units, Aux gas 20arbitrary units, tube lens 85 and collision gas 1.2 mTorr. SRMchromatograms of kynurenine (Q1: 209.2>Q3:94.0) and internal standard(Q1: 215.3>Q3:98.2) were collected for 90 sec. The peak area wasintegrated by Xcalibur Quan software. The ratios between the kynureninegenerated in the reaction and 2D6-Kynurenine spiked-in internal standardwere used to generate percentage inhibition and IC₅₀ values. Compoundswere titrated and IC₅₀'s were calculated by 4 parameter sigmoidal curvefitting formula.

The biological activity data of selective compounds using the IDO1 humanwhole blood assay described above are summarized in the table below.

Ex. Whole Blood IC₅₀ Form # (nM) Screened 2 186 Neutral 7 345 TFA Salt19 336 Neutral 21 797 Neutral 27 21 TFA Salt 28 253 TFA Salt 30 795Neutral 32 738 Neutral 33 1877 Neutral 35 1604 TFA Salt 63 70 Neutral 701712 Neutral 77 333 Neutral 85 219 Neutral 88 57 Neutral

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula (Ib), or a pharmaceuticallyacceptable salt thereof:

wherein: R¹ is selected from: (1) C₃₋₆ cycloalkyl, optionallysubstituted with 1-3 substituents independently selected from (a)halogen, (b) —O—C₁₋₆ alkyl and (c) C₁₋₆ alkyl optionally substitutedwith 1-3 halogens, (2) phenyl, optionally substituted with 1-3substituents independently selected from (a) halogen, (b) —CN, (c)—O—C₁₋₆ alkyl and (d) C₁₋₆ alkyl optionally substituted with 1-3halogens, (3) a bicyclic ring comprising a phenyl fused to aC₄₋₇cycloalkyl, wherein the bicyclic ring is optionally substituted withhalogen or C₁₋₆ alkyl, and (4) a heterocyclyl selected from (a) asaturated 4-7 membered monocyclic heterocyclyl, (b) a partiallyunsaturated 4-7 membered monocyclic heterocyclyl, (c) an aromatic 4-7membered monocyclic heterocyclyl, and (d) a 6-9 membered fused bicyclicring containing one or more heteroatoms selected from N, O, and S ineither of the rings, wherein the heterocyclyl is optionally substitutedwith 1-3 substituents independently selected from (a) halogen, (b) —CNand (c) C₁₋₆ alkyl; R² is selected from: (1) C₁₋₆ alkyl, optionallysubstituted with 1-3 substituents independently selected from (a)halogen and (b) C₃₋₆ cycloalkyl, (2) C₃₋₆ cycloalkyl, optionallysubstituted with 1-3 substituents independently selected from (a)halogen and (b) C₁₋₆ alkyl optionally substituted with NH₂, (3) phenyl,optionally substituted with 1-3 substituents independently selected from(a) halogen and (b) C₁₋₆ alkyl, (4) a bicyclic ring comprising a phenylfused to a C₄₋₇cycloalkyl, optionally substituted with halogen or C₁₋₆alkyl, (5) S(O)₂-aryl, and (6) a heterocyclyl selected from (a) asaturated 4-7 membered monocyclic heterocyclyl, (b) a partiallyunsaturated 4-7 membered monocyclic heterocyclyl, and (c) an aromatic4-7 membered monocyclic heterocyclyl, wherein the heterocyclyl isoptionally substituted with 1-3 substituents independently selected from(a) halogen and (b) C₁₋₆ alkyl; R³ is selected from (1) H, (2) fluoro,(3) methyl, (4) ethyl, (5) —CH₃—OH, and (6) —C═N—C(CH₃)₃; and each of R⁴and R⁵ is independently selected from (1) H, (2) halogen, (3) —OH, and(4) methyl.
 2. A compound selected from the group consisting of, or apharmaceutically acceptable salt thereof:N-(4-(1-butyramidocyclobutyl)phenyl)-3-chlorobenzamide,3-chloro-N-(4-(1-(4-cyanobenzamido)cyclobutyl)phenyl)benzamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)pyrazine-2-carboxamide,3-chloro-N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)pyridine-2-carboxamide,4-chloro-N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)pyridine-2-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-1-methyl-1H-imidazole-2-carboxamide,6-chloro-N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)pyridine-3-carboxamide,4-chloro-N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-3-fluorobenzamide,5-chloro-N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)pyridine-2-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-3,4-difluorobenzamide,3,4-dichloro-N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)benzamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-1,3-oxazole-2-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-1-methyl-1H-pyrazole-3-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-1,3-thiazole-4-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-1,3-thiazole-2-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)-1,3-oxazole-4-carboxamide,N-(4-{1-[(4-chlorobenzene-1-carbonyl)amino]cyclobutyl}phenyl)pyrimidine-5-carboxamide,N-(1-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}cyclobutyl)pyrimidine-5-carboxamide,3-chloro-N-(4-(1-(4-chlorobenzamido)cyclobutyl)phenyl)benzamide,3-chloro-N-(4-(1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide,1-(4-(3-chlorobenzamido)phenyl)cyclobutane-1-carboxylic acid,3-chloro-N-(4-{1-[(4-chlorophenyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(2,4-difluorophenyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(3,4-difluorophenyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(6-chloropyridin-3-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(5-fluoropyridin-2-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(6-fluoropyridin-3-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-{4-[1-(cyclohexylcarbamoyl)cyclobutyl]phenyl}benzamide,3-chloro-N-(4-{1-[(2-ethylcyclopropyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-[4-(1-{[(1R,2R)-2-(trifluoromethyl)cyclopropyl]carbamoyl}cyclobutyl)phenyl]benzamide,3-chloro-N-(4-{1-[(4,4-difluorocyclohexyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(oxan-4-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(2-ethoxycyclopropyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-[4-(1-{[2-(difluoromethyl)cyclopropyl]carbamoyl}cyclobutyl)phenyl]benzamide,3-chloro-N-(4-{1-[(3,3-difluorocyclobutyl)carbamoyl]cyclobutyl}phenyl)benzamide,N-(4-{1-[(bicyclo[1.1.1]pentan-1-yl)carbamoyl]cyclobutyl}phenyl)-3-chlorobenzamide,3-chloro-N-(4-{1-[(oxan-3-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(1-cyclopropylethyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(2,2-dimethyloxan-4-yl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-[4-(1-{[1-(oxolan-2-yl)ethyl]carbamoyl}cyclobutyl)phenyl]benzamide,3-chloro-N-[4-(1-{[1-(2,2,2-trifluoroethyl)azetidin-3-yl]carbamoyl}cyclobutyl)phenyl]benzamide,3-chloro-N-(4-(1-((2-ethoxypropyl)carbamoyl)cyclobutyl)phenyl)benzamide,3-chloro-N-(4-{1-[(2-methylcyclopropyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(3,3,3-trifluoropropyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(cyclopropylmethyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-{1-[(2,2,2-trifluoroethyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-{4-[1-(ethylcarbamoyl)cyclobutyl]phenyl}benzamide,3-chloro-N-[4-(1-{[(3S)-oxolan-3-yl]carbamoyl}cyclobutyl)phenyl]benzamide,3-chloro-N-[4-(1-{[(3R)-oxolan-3-yl]carbamoyl}cyclobutyl)phenyl]benzamide,3-chloro-N-(4-{1-[(phenylsulfonyl)carbamoyl]cyclobutyl}phenyl)benzamide,5-methyl-N-(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)-1,2,3-thiadiazole-4-carboxamide,4-(aminomethyl)-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide,3-methyl-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}-1,2-oxazole-5-carboxamide,2-ethyl-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}-1,3-oxazole-4-carboxamide,N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}imidazo[1,2-b]pyridazine-2-carboxamide,N-(3-chloro-2-fluorophenyl)-4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzamide,N-cyclohexyl-4-{1-[(5-fluoropyridin-2-yl)carbamoyl]cyclobutyl}benzamide,N-(4,4-difluorocyclohexyl)-4-{1-[(5-fluoropyridin-2-yl)carbamoyl]cyclobutyl}benzamide,3-chloro-N-(4-(3-fluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide,3-chloro-N-(4-(3,3-difluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)benzamide,3-chloro-N-[4-(1-{[(1S,2R)-2-ethoxycyclopropyl]carbamoyl}-3,3-difluorocyclobutyl)phenyl]benzamide,3-chloro-N-(4-{1-[(2-ethoxycyclopropyl)carbamoyl]-3,3-difluorocyclobutyl}phenyl)benzamide,3-chloro-N-[4-(1-{[(1R,2S)-2-ethoxycyclopropyl]carbamoyl}-3,3-difluorocyclobutyl)phenyl]benzamide,3-chloro-N-[4-(1-{[(1R,2R)-2-ethoxycyclopropyl]carbamoyl}-3,3-difluorocyclobutyl)phenyl]benzamide,3-chloro-N-(4-{3,3-difluoro-1-[(3,3,3-trifluoropropyl)carbamoyl]cyclobutyl}phenyl)benzamide,3-chloro-N-(4-((cis)-1-((4-fluorophenyl)carbamoyl)-3-hydroxycyclobutyl)phenyl)benzamide,3-chloro-N-(4-((1r,3r)-1-((4-fluorophenyl)carbamoyl)-3-hydroxy-3-methylcyclobutyl)phenyl)benzamide,N-(4-(3,3-difluoro-1-((4-fluorophenyl)carbamoyl)cyclobutyl)phenyl)-3-fluorobenzamide,3-cyano-N-(4-{3,3-difluoro-1-[(4-fluorophenyl)carbamoyl]cyclobutyl}phenyl)benzamide,4-chloro-N-(4-{3,3-difluoro-1-[(4-fluorophenyl)carbamoyl]cyclobutyl}phenyl)pyridine-2-carboxamide,5-chloro-N-(4-{3,3-difluoro-1-[(4-fluorophenyl)carbamoyl]cyclobutyl}phenyl)pyridine-3-carboxamide,N-(4-{3,3-difluoro-1-[(4-fluorophenyl)carbamoyl]cyclobutyl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide,4-fluoro-3-methyl-N-(4-(1-(propylcarbamoyl)cyclobutyl)phenyl)benzamide,3-chloro-4-fluoro-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide,3-chloro-5-fluoro-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide,3,5-dichloro-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide,3,4-dichloro-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide,3-chloro-N-(2-fluoro-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide,3-chloro-N-(2-(hydroxymethyl)-4-(1-((3,3,3-trifluoropropyl)carbamoyl)cyclobutyl)phenyl)benzamide,N-(2-[(E)-(tert-butylimino)methyl]-4-{1-[(3,3,3-trifluoropropyl)carbamoyl]cyclobutyl}phenyl)-3-chlorobenzamide,3-chloro-N-(4-(1-((4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbamoyl)cyclobutyl)phenyl)benzamide,andN-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide.3. A composition which comprises an inert carrier and a compound ofclaim 1 or a pharmaceutically acceptable salt thereof.
 4. A method fortreating an IDO-associated disease or disorder in a mammalian subjectwhich comprises administering to the subject an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 5. Amethod for treating an IDO-associated disease or disorder in a mammaliansubject which comprises administering to the subject an effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereofin combination with another anti-cancer agent.
 6. The method of any ofclaim 4, wherein the IDO-associated disease or disorder is a cancer,viral infection, HCV infection, depression, neurodegenerative disorders,trauma, age-related cataracts, organ transplantation, and autoimmunediseases.
 7. The method of claim 6, wherein the cancer is selected froma cancer of the colon, pancreas, breast, prostate, lung, brain, ovary,cervix, testes, renal, head and neck, lymphoma, leukemia, and melanoma.